Detection of atrial fibrillation

AF can be recognized on the electrocardiogram (ECG) by an irregular ventricular rhythm without consistent P waves ( Fig. 29.1) [1]. Epidemiological studies using short-term (often one single) ECG recording and symptoms have estimated the prevalence of AF in the population at 0.5–1% [2–5]. Continuous ECG monitoring of AF patients suggests that more than half of AF episodes are not detected by standard ECG recordings, even in symptomatic AF patients [6–8]. Hence, the ‘true’ prevalence of AF may be closer to 2% of the population [8]. As the population ages, it is expected that the number of patients with AF will double or triple in the next few decades ( Fig. 29.2).

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Figure 29.1

12-lead electrocardiogram demonstrating atrial fibrillation. Note the irregular ventricular response rate and the fine baseline oscillations due to ‘f ’ waves. No consistent P-wave activity can be seen.

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Figure 29.2

Projected number of adults with atrial fibrillation in the United States by 2050. ATRIA, AnTicoagulation and Risk Factors In Atrial Fibrillation. Data from Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285: 2370–5 and Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114: 119–25.

Prevalence of atrial fibrillation

The prevalence of AF increases with age. Less than 0.5% of 40–50-year-olds suffer from AF, while an estimated 5–15% of the population present with AF at the age of 80 years [3, 9–11] ( Fig. 29.3). Men are more often affected than women, and the age of diagnosis is later in women, but women with AF appear to be more prone to AF-related complications [4, 12]. The recurrent, initially often self-terminating nature of the arrhythmia [13] translates to a lifetime risk of AF around 25% in current 40-year-olds [14, 15]. Furthermore, in the Western world the age-adjusted prevalence of AF has increased over the past decades [2, 3, 10].

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Figure 29.3

Increasing prevalence of atrial fibrillation among first-ever hospital admissions between 1986 and 1995. The greatest increase is seen among the elderly. (A) Men; (B) women. Reproduced with permission from Stewart S, Hart CL, Hole DJ, et al. Population prevalence, incidence, and predictors of atrial fibrillation in the Renfrew/Paisley study. Heart 2001; 86: 516–21.

Incidence of atrial fibrillation

Similar to AF prevalence, its incidence appears to increase with age, is higher in men than in women [2], and has risen in the last two decades [10], varying from 1.6–1.0% per annum [11] to 0.54 cases per 1000 person years [2]. A high proportion of undiagnosed AF suggests a large potential overlap between newly detected ‘prevalent’ and truly ‘incident’ AF in the context of scheduled surveys using ECG recordings.

Ethnicity and atrial fibrillation

The prevalence and incidence of AF in non-white populations are less well studied, but lower values were reported for Asians and African Americans [16]. In the health survey of 664,754 US veterans, white men were significantly more likely to have AF compared to all races but Pacific Islanders (odds ratios vs. blacks, 1.84; vs. Hispanics, 1.77; vs. Asians, 1.41; vs. Native Americans, 1.15; p < 0.001) [17]. Whites were more likely to have valvular heart disease, coronary artery disease, and congestive heart failure; blacks had the highest hypertension prevalence; Hispanics had the highest diabetes prevalence associated with AF. Racial differences remained after adjustment for age, body mass index, and other comorbidities.

Predisposing clinical conditions

AF is associated with a variety of cardiovascular conditions that may perpetuate the arrhythmia [4, 12, 24, 25]. These conditions may also be markers for global cardiovascular risk [26] and/or cardiac damage rather than causative factors.

Hypertension ( Chapter 13) is the most common underlying condition in AF patients, found in approximately 2/3 of all AF patients in different surveys ( Fig. 29.6) [4]. Inadequate control of blood pressure is a risk factor for incident (first diagnosed) AF in hypertensive patients and for AF-related complications such as stroke and systemic thromboembolism, even in anticoagulated populations [27–29].

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Figure 29.6

Types of atrial fibrillation by concomitant pathology in the Euro Heart Survey. Modified with permission from Nieuwlaat R, Capucci A, Camm AJ, et al. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005; 26: 2422–34.

Antihypertensive treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is more effective in preventing incident AF than therapy with beta-receptor blockers or calcium antagonists in patients with left ventricular (LV) dysfunction or LV hypertrophy, despite similar reductions in blood pressure [30, 31] but less so in patients with well-controlled hypertension and without structural heart disease [32]. This is because the former may prevent atrial remodelling (cellular hypertrophy and atrial fibrosis) in patients prone to such changes (see ‘Upstream’ therapy, p.1113).

Heart failure (Chapter 23), defined as heart failure with dyspnoea on exertion (New York Heart Association (NYHA) classes II–IV) is found in 30% of AF patients [4, 12], and AF is found in 5–50% of heart failure patients [33]. The prevalence of AF clearly increases with the clinical severity of heart failure, with an AF prevalence of almost 50% in patients with NYHA IV heart failure ( Fig. 29.7) [34].

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Figure 29.7

Prevalence of atrial fibrillation in studies of heart failure. Reproduced with permission from Savelieva I, Camm AJ. Atrial fibrillation and heart failure: natural history and pharmacological treatment. Europace 2004; 5 (Suppl.1): S5–19.

Heart failure can be either a consequence of AF (tachycardiomyopathy or decompensation in acute-onset AF) or a cause for the arrhythmia (by atrial pressure and volume overload, or chronic neurohumoral stimulation). In most patients, both conditions sustain each other to different degrees. Importantly, new-onset AF appears to be an independent predictor of death and prolonged intensive care unit stay in non-selected heart failure patients [35], and exercise performance is markedly reduced in patients with heart failure and permanent AF [36].

Of note, many pharmacological treatments that prevent death in heart failure trials (ACE inhibitors, beta-blockers) also prevent new-onset AF (see ‘Upstream’ Therapy, p.1113) [34]. The common myocardial damage mechanisms that precipitate AF and heart failure (see Chapter 23) may suggest that AF is an ‘atrial cardiomyopathy’. Diastolic LV dysfunction is also strongly correlated with the incidence of AF.

Tachycardiomyopathy is a form of LV dysfunction caused by AF: rapid irregular rate and loss of atrial contractile function results in severe LV dysfunction in selected patients with AF in the absence of structural heart disease. Similar effects have been described for other incessant tachycardias, including atrial and atrioventricular (AV) nodal tachycardia [37], and right ventricular outflow tract tachycardia [38]. Tachycardiomyopathy should be suspected when there is a fast ventricular rate and LV dysfunction but no signs for structural heart disease. Tachycardiomyopathy is confirmed when LV function is restored with adequate rate control or maintenance of sinus rhythm ( Fig. 29.8). Recovery of LV function may require several weeks. In some patients, only repeated measurements of LV function over time can distinguish between mild forms of ventricular cardiomyopathy complicated by AF and tachycardiomyopathy.

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Figure 29.8

Resolving atrial fibrillation rate-related cardiomyopathy. This young man presented with atrial fibrillation and an average heart rate of 125bpm. He had been unwell for several months but was not aware of his heart rate during this time (A). Four weeks after cardioversion to sinus rhythm his heart size had reduced to normal (B).

Valvular heart disease ( Chapter 21), especially mitral valve stenosis and regurgitation, induces left atrial (LA) pressure or volume overload that can provoke AF. Secondary to the improved earlier treatment of valvular heart disease and the prevention of rheumatic heart disease, severe mitral valve disease has become less common in Europe. The contribution of mild valvular heart disease to the development of AF is less clear, but some degree of valvular heart disease is found in approximately 30% of AF patients [4, 12].

Cardiomyopathies ( Chapter 18) including the primary electrical cardiac diseases ( Chapter 9 and 30) [39] carry a high individual risk for AF. In fact, sudden death and AF are clearly associated in epidemiological studies, suggesting the possibility of a common mechanism for both arrhythmias. The genetically determined cardiomyopathies comprise hypertrophic, dilated, and right ventricular cardiomyopathy. In addition ‘electrical cardiomyopathies’ such as long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic VT should be considered.

The high individual risk for AF at younger ages [40–43] probably explains why relatively rare cardiomyopathies are found in 10% of AF patients [4, 12]. Genetic studies suggest that a small proportion of patients with ‘lone AF’ are actually mutation carriers for ‘primary electrical’ cardiomyopathies [44].

With the possible exception of catecholaminergic ventricular tachycardia (VT), all genetically determined cardiomyopathies carry a risk for AF [41, 45]. In the long QT syndromes, ‘AF’ appears to be caused by after-depolarizations and prolongation [46, 47], rather than shortening of the action potential [48] (atrial ‘torsade’). Occasionally, ‘twisting’ of the P waves during atrial arrhythmias has been reported in long QT syndrome (29.1). In short QT syndrome, AF appears to be even more prevalent than ventricular arrhythmias [49, 50].

There is a high prevalence AF in Brugada syndrome ( Chapter 9) [42] but the mechanism is not delineated. It may be linked in some patients to mutations in the sodium channel (SCN5A) gene, and conduction slowing. In hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy (ARVC) ( Chapter 18), a mixture of altered myocardial structure, changes in haemodynamic function, and primary electrical changes appear to cause AF [51, 52]. The reported association between ventricular pre-excitation or Wolff–Parkinson–White syndrome and AF (29.2) may be either due to the more severe symptoms of AF in patients with rapid conduction of atrial activity via the bypass tract, or due to a common genetic cause ( Table 29.4).

Atrial septal defects ( Chapter 10) are associated with AF in 10–15% of patients according to earlier surveys [40]. This association has important clinical implications in the antithrombotic management of stroke or transient ischaemic attack (TIA) survivors with an atrial septal defect. In patients with large shunt volumes and/or a high atrial load due to the septal defect, AF may be secondary to pressure and volume overload. In others, the association between AF and septal defects points to a common abnormality (e.g. a genetic predisposition) that predisposes to both ASD and AF.

Other congenital heart defects ( Chapter 10) are often associated with AF. Patients with single ventricles, atrial repair (Mustard operation) of a transposition of the great arteries, or after a Fontan procedure are at especially high risk for AF. Altered atrial anatomy, either due to the primary defect or secondary to repair surgery, and the ensuing altered atrial haemodynamics, may be one of the main predisposing factors for AF. AF can be highly symptomatic in these patients, and is often difficult to treat.

Coronary artery disease (CAD) ( Chapters 16 and 17) is present in 20% of the AF population. Studies that recruited patients in hospital usually have higher prevalence of coronary heart disease than when outpatients are enrolled, most likely secondary to the relatively high likelihood of in-hospital treatment of coronary heart disease [53]. Whether CAD per se predisposes to AF is not known, given that the association between AF and CAD may be mediated via heart failure in survivors of a myocardial infarction, or by shared risk factors, such as hypertension. AF is rare in patients with stable CAD and preserved LV function, but indicates those with a poor prognosis after a myocardial infarction [54].

Thyroid dysfunction is an important cause of AF. In recent surveys, only a relatively small percentage of the AF population (10% in Germany, a country with a high prevalence of goitre due to iodine deficiency) presents with apparent hyper- or hypothyroidism [4, 12]. In a population-based study of 5860 subjects aged 65 years and older, the biochemical finding of subclinical hyperthyroidism is associated with AF on the resting ECG, and even in euthyroid subjects with normal serum thyroid-stimulating hormone (TSH) levels, serum free T4 concentration is independently associated with AF [55].

Obesity is found in 25% of AF patients [4]. In meta-analysis of the population-based cohort studies, obese individuals have an associated 49% increased risk of developing AF compared to non-obese individuals [56]. Obesity is associated with hypertension, sleep apnoea, chronic obstructive airways disease, and diabetes mellitus, among others, and most likely is a marker for cardiovascular risk that associates, among other events, with AF.

A proportion of patients with metabolic syndrome (see Chapter 15) develop AF. An apparent correlation between the presence of metabolic syndrome and increased susceptibility to AF during a mean follow-up of 4.5 years has recently been demonstrated in a large (>28,000 subjects) community-based cohort in Japan [57]. Again, this association may reflect that metabolic syndrome summarizes several of the known conditions that predispose to AF.

Sleep apnoea is associated with an atrial pressure rise and dilatation and may predispose to AF [58]. The retrospective cohort study of 3542 Olmsted County adults who were referred for a diagnostic polysomnogram, has found that obesity and the magnitude of nocturnal oxygen desaturation, which is an important pathophysiological consequence of sleep apnoea, were independent risk factors for new incident AF in individuals <65 years of age [59].

Tall stature is associated with AF [60]. The mechanisms are unclear, but mechanical distension of pulmonary veins (PVs) and LA dilatation are possible.

Diabetes mellitus, when defined as a medical condition that requires treatment, is found in 20% of AF patients. It is conceivable that badly controlled diabetes mellitus may contribute to atrial cell death and ‘structural remodelling’, and thereby contribute to the perpetuation of AF [61].

Chronic obstructive pulmonary disease is found in 10–15% of AF patients [62]. In some patients, pulmonary disease may rather be a marker for cardiovascular risk in general than a specific predisposing factor for AF. Cancer of the bronchus may also present with AF.

Chronic renal disease (see Chapter 15), measured as renal dysfunction, is present in 10–15% of AF patients. Renal failure appears to increase the risk for AF-related complications, especially cardiovascular complications. Renal failure, diabetes mellitus, and chronic obstructive pulmonary disease are more prevalent in patients with permanent AF.

Initiation and maintenance of atrial fibrillation

The aetiology of AF is complex, and several different factors contribute to changes that promote focal atrial activity or one of the different forms of re-entry in the atria. Several experimental models have helped to dissect AF-induced pathophysiological changes that contribute to the perpetuation of AF. Fig. 29.11 summarizes several of the known vicious circles that contribute to the initiation and perpetuation of AF. In a given patient (or a given experimental model), different pathophysiological changes may have more or less impact. These vicious circles are important because their interruption by therapeutic interventions (drugs, lifestyle changes, or catheter ablation) is probably the main determinant of treatment success for rhythm-control therapies.

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Figure 29.11

Vicious circles that contribute to the genesis of atrial fibrillation. Initiation and perpetuation of atrial fibrillation is caused by multiple factors in the vast majority of patients. Many of these are self-sustaining, i.e. they are part of ‘vicious circles’ that accelerate the progression of atrial fibrillation with each episode. The figure illustrates four of these vicious circles. Rapid atrial rates, e.g. caused by atrial fibrillation, atrial flutter, or atrial tachycardias, cause intracellular calcium overload. To protect itself against calcium-induced cell death, cardiomyocytes activate a ‘survival programme’ to extrude as much calcium as possible. This is done by shortening atrial action potential duration and refractoriness (‘electrical remodelling’). Although preventing cell death, this mechanism reduces wave length and contributes to atrial fibrillation recurrence after premature atrial activations. Focal activity within the pulmonary veins, a frequent trigger of ‘lone’ paroxysmal atrial fibrillation, can be caused by stretch within the atrial–atrial fibrillation junction or by calcium load in cardiomyocytes leading to spontaneous calcium release and afterdepolarizations, especially in the presence of sympathetic stimulation. Via calcium load, sympathetic activation, and increased stretch at the LA (left atrial)–PV (pulmonary vein) junction this mechanism is prone to a second vicious circle. Atrial fibrillation-induced structural changes occur already after several hours of atrial fibrillation. Many of these changes are mediated via activation of the renin–angiotensin system due to atrial stretch, atrial pressure increase, and peripheral hypovolemia. Activation of renin–angiotensin–aldosterone system (RAAS) will increase extracellular matrix formation, lead to cardiomyocyte isolation, create localized conduction barriers which will facilitate reentry within the atria, and thereby reduce atrial wave length. Rapid and irregular rate during atrial fibrillation, in conjunction with loss of atrial contractile function, reduce cardiac output and can cause left ventricular (LV) dysfunction. The systemic response to LV dysfunction is, again, RAAS activation, sympathetic activation (with in turn even more rapid ventricular rates), and thereby perpetuation of atrial fibrillation. Last but not least, activation of any of the cellular changes involved in these vicious circles can activate expression of prothrombotic factors in atrial endothelium. As delineated later in the text, therapeutic approaches to disrupt each of these vicious circles exist: electrical remodelling: antiarrhythmic drugs; focal activity: pulmonary vein isolation, structural changes: upstream therapy; LV dysfunction: rate control therapy (and, to some extent, successful rhythm control therapy). Modified with permission from Koebe J, Kirchhof P. Novel non-pharmacological approaches for antiarrhythmic therapy of atrial fibrillation. Europace 2008; 10: 433–7.

Focal activity in the pulmonary veins

Focal ectopic activity in the PVs was first described in patients with AF [93]. Especially in the early phases of AF and in patients with so-called ‘lone AF’ (i.e. AF without concomitant conditions that might explain the arrhythmia), AF episodes are often initiated by rapid focal electrical activity originating from within the PV, the junction between PVs and posterior LA, and to a lesser extent in other regions of the venous parts of the atria [93]. Abnormal calcium release may be driving these focal discharges [97], although re-entry within the PV myocardium may also contribute to the initiation of ‘focal activity’ in the PVs [98]. Ablation therapy of AF which targets these focal sources has proven effective in its prevention (see Catheter ablation strategies, p.1121) [99].

Electrical remodelling

The process of AF-induced ‘electrical remodelling’ was first described in goats with pacing-induced AF ( Fig. 29.12) [100]. In essence, the atrial myocardium responds to the high atrial rate in the fibrillating atria by shortening of atrial refractoriness and atrial action potential duration. This is most likely a ‘cellular survival mechanism’ that helps to extrude excess intracellular calcium from the rapidly activated atrial myocardial cells [101]. On the molecular level, an altered expression and regulation of proteins involved in potassium and calcium channels reduces calcium currents and increases potassium currents ( Fig. 29.13) [102, 103].

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Figure 29.12

Atrial fibrillation ‘begets’ atrial fibrillation. In the control state a short burst of atrial pacing in this goat model induces a brief episode of rapid atrial fibrillation. Repeated re-induction of atrial fibrillation leads to progressive acceleration of the fibrillatory impulses and longer duration of the arrhythmia. After 2 weeks atrial fibrillation which is induced does not terminate spontaneously. Reproduced with permission from Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995; 92: 1954–68.

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Figure 29.13

Atrial action potential recorded in cardiomyocytes isolated from two patients undergoing open-heart surgery. Patient 1 (blue) had no history of atrial fibrillation. Patient 2 (red) was in atrial fibrillation at the time of the operation. Atrial fibrillation-induced ‘electrical remodelling’ can be seen as shortening of the action potential and as the less negative resting membrane potential. Abbreviations indicate the main currents that contribute to action potential shortening. Modified with permission from Ravens U, Cerbai E. Role of potassium currents in cardiac arrhythmias. Europace 2008; 10: 1133–7.

In addition to acceleration of repolarization (action-potential shortening), the resting membrane potential is more positive in chronic AF, most likely secondary to a constitutive activation of I_KACh [104]. However, shortening of the atrial action potential not only preserves viability during AF, but also renders the atria prone to recurrent AF. The atrial action potential normalizes in the first few weeks, and possibly even in the first few days, after restoration of sinus rhythm.

The concept of electrical remodelling provides a pathophysiological rationale for the use of drugs that prolong the atrial action potential to prevent recurrences of AF after cardioversion, i.e. in atria that underwent the process of electrical remodelling [105–108]. Time-dependent recovery from electrical remodelling in sinus rhythm suggests that therapy with ion channel-blocking agents may be stopped once electrical remodelling has been reversed [108].

Atrial fibrillation-induced contractile dysfunction

Continuous electrical reactivation of atrial cardiomyocytes results in reduced duration of electrical diastole, increased calcium influx through the sarcolemmal membrane, increased calcium release from the sarcoplasmic reticulum, and consequently a rapid intracellular calcium overload in the atrial myocardium [109]. The resulting altered expression and function of calcium-handling proteins and the ensuing altered regulation of the contractile apparatus reduces atrial contractile function and increases atrial size [110]. These changes persist for several weeks after restoration of sinus rhythm (atrial stunning)[111]. Contractile dysfunction suggests an important role for intracellular calcium overload in the maintenance of AF [112] and has also been regarded as a reason for anticoagulation in the first weeks after cardioversion [1].

Atrial fibrillation-induced structural changes

The relatively high AF recurrence rate in the active-treatment arms of ion channel-blocking drug trials already suggests that electrical remodelling is not the only factor that maintains AF and/or provokes its recurrence. AF induces an increased expression of extracellular matrix proteins and increased atrial fibrosis ( Fig. 29.14) [113]. These changes result in conduction slowing in the atria, and in electrical isolation of atrial cardiomyocytes, even prior to development of AF [114]. The molecular signalling pathways that mediate these structural changes are not fully understood, but the angiotensin system is activated, sympathetic stimulation is increased, a ‘fetal’ gene expression programme is activated, and thrombogenic molecules are expressed in the endothelium in AF [115]. Inhibition of either the ACE or the angiotensin II receptor in the heart can prevent some of these AF-induced changes [116].

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Figure 29.14

Atrial myocardium (Masson's trichrome stain). Atrial fibrillation induces an increased expression of extracellular matrix proteins and increased atrial fibrosis. AF, atrial fibrillation; SR, sinus rhythm. (Courtesy of Andreas Göette, University hospital Magdeburg, Germany.)

The lack of intracellular ATP donators, possibly due to mitochondrial dysfunction, may contribute to extracellular matrix formation, cellular dysfunction, and potentially to cell death, and de-differentiation of atrial myocardium [115, 117]. This is one cause of major metabolomic changes in atrial tissue from AF patients [118] and animal models of AF [119]. The antifibrillatory effect of ACE inhibitors, ARBs, and statins is most likely explained by the effects of these drugs on AF-induced structural changes. Whether inflammation of the atrial myocardium [120, 121], identifiable by increased content of inflammatory cells in atrial tissue, and in part by increased C-reactive protein (CRP) levels in the blood of patients with AF [122, 123], is an independent process or not, is unknown.

Ageing and atrial fibrillation

The prevalence of AF is clearly age-dependent (see Prevalence of atrial fibrillation, p.1070). Ageing is associated with an increased isolation of cardiomyocytes through altered expression of connexins and increased development of fibrous septa between atrial muscle fibres [124]. Denatured atrial natriuretic peptide creates amyloid-like deposits that also lead to fibre separation. AF-induced mitochondrial DNA deletions which are associated with altered mitochondrial energy production are comparable to the DNA alterations found in ageing myocardium [125]. In this regard, ageing is associated with some of the changes that are found as a structural consequence of AF. Conversely, the structural changes found in AF may be a form of accelerated ‘AF-induced’ ageing of the atrial myocardium. A mild form of genetically conferred accelerated ageing (progeria) is also associated with AF [126].

Intracellular calcium overload

Intracellular calcium overload due to the loss of electrical diastole occurs even after short episodes of AF. Calcium has several major roles in the cardiomyocyte, including initiation and regulation of cellular contraction by binding to troponins, regulation of cellular proteins, protein kinases, and subsequent regulation of intracellular signalling pathways, and regulation of sarcolemmal and sarcoplasmic reticulum electrical function. Intracellular calcium overload may be the initial event that triggers some of the known AF-induced electrical [127], contractile [128], structural [129], metabolomic, and inflammatory changes [130].

Atrial stressors that predispose to atrial fibrillation

Some of the pathophysiological responses to ‘atrial stressors’ that predispose to AF have been delineated in experimental studies: dogs in which ventricular pacing induces heart failure are prone to conduction slowing and inducible AF [132, 133]. In a sheep model of early-onset arterial hypertension, inducible AF was associated with electrical isolation of atrial cardiomyocytes, increased formation of extracellular matrix, and conduction disturbances without evidence for action-potential shortening [114]. Chronic dilatation of the atria secondary to chronic pressure and/or volume overload of the atria may induce these structural changes that appear to precede AF, possibly related to AF in the setting of severe valvular heart disease or heart failure [12, 134, 135].

High-level endurance sports may be sufficient to predispose to AF, most likely via chronic atrial dilatation [58, 136]. Atrial ischaemia may also contribute to the initiation of AF. In another study in dogs with ‘spontaneous’ sustained AF, action-potential shortening was found prior to AF, suggesting that these electrical changes can also form prior to AF [109]. It is conceivable that many of the vicious circles mentioned earlier ( Fig. 29.11) are activated prior to AF and contribute to its initiation. Retrospective analyses from randomized studies [34] suggest that structural changes that precede AF may be a reasonable target for primary prevention of AF.

Genetic alterations found in inherited cardiomyopathies (see Chapter 9)

Sudden death and ventricular fibrillation in the young are often caused by inherited cardiomyopathies [138]. Many of the proteins that are mutated in these diseases are also expressed in the atria, and the same electrical abnormalities which are arrhythmogenic in the ventricles can cause AF. Patients with short QT syndrome, i.e. a genetic cause for short cardiac action potentials and a QT interval <0.33s, are at high risk for AF, e.g. detected by inappropriate defibrillator discharges [49, 50]. The first identified mutation found in a family with AF affects a gene that is also altered in the short QT syndrome (KCNQ1) [48]. Short QT syndrome can probably be considered a ‘genetic’ cause of atrial action potential shortening (see Electrical remodelling, p.1079).

More recently, several groups have found an increased risk of AF in patients with long QT syndrome [41, 43, 46], polymorphisms associated with QT prolongation co-associate with AF [139], and mutations in long QT syndrome-causing genes are found in approximately 5% of patients with ‘idiopathic’ AF [44]. The limited available data suggest that prolongation of the atrial action potential and after-depolarizations cause AF in these patients [46] (29.1). Similar mechanisms may be present in patients with a nonsense mutation in the Kv1.5 gene responsible for the ‘atrial-specific’ potassium current I_Kur [135].

The pathophysiological factors that cause AF and other supraventricular arrhythmias in Brugada syndrome are less well established, but the prevalence of AF is high [42]. It is conceivable that the combination of a ‘Brugada-type’ ECG with AF is indicative of patients with a sodium channel mutation [44, 140], and that either conduction slowing in the atria [141–143] and/or prolongation of the atrial action potential and after-depolarizations (‘atrial torsade de pointes’) [46, 144] cause AF in such patients.

Sodium channel mutations have also been identified in patients with ‘lone’ AF [44, 145] and in a large family suffering from heart failure and atrial fibrillation [146]. Mutations in the cardiac ryanodine receptor, the calcium release channel in the sarcoplasmic reticulum, have been associated with AF and catecholaminergic VT [147]. Whether AF in hypertrophic cardiomyopathy is mediated via electrical changes, e.g. secondary to altered calcium handling by the mutated sarcomeric proteins, or a consequence of the increased atrial pressure and volume load in obstructive forms of the disease, has not been convincingly studied. A small group of patients suffer from a genetic abnormality in the PRKAG protein. Clinically, these patients carry a combination of AF, ventricular pre-excitation, and atypical LV hypertrophy [148, 149].

Other genetic abnormalities associated with atrial fibrillation

Somatic, i.e. ‘heart-restricted’ mutations in connexin 40 have been identified in a small series of patients in whom atrial tissue could be genetically studied [150], and a frameshift mutation in the gene coding for the atrial natriuretic peptide (ANP) [151] has recently been identified in patients with ‘lone’ AF. Hence, either genetically conferred conduction disturbances or genetically-conferred altered ANP signalling and/or hypertension may cause AF.

In addition to these genetic alterations with more or less known functional consequences, a population-wide study has associated a common variant in the PITX2 gene with AF [152]. This finding was replicated in other cohorts. PITX2 is an important regulator of cardiac development including formation of the LA and pulmonary tissue, and a part of the PVs [153, 154]. Another study found an association with TBX5, another regulator of cardiac development, and AF in patients with the Holt–Oram syndrome [155], and a transgenic model with enhanced atrial activity of TGFβ1 predisposes to AF, atrial fibrosis and conduction slowing [156–159].

Silent atrial fibrillation

Silent AF may be found incidentally during routine physical examinations, pre-operative assessments, occupation assessments, or population surveys. The prevalence of sustained silent AF in epidemiology studies is believed to be about 25–30% of AF patients [163].

In some cases, silent AF is diagnosed only after a complication such as stroke or heart failure has occurred. Thus, in the Framingham Study database, AF was found incidentally in about 18% of admissions for stroke and subsequently diagnosed within 2 weeks in another 4.4% [164]. Therefore, a thorough screening for AF is needed in patients with such complications. Given that detection of AF has therapeutic consequences (e.g. anticoagulation), prolonged Holter ECG monitoring is recommended in such patients with suspected asymptomatic AF.

Wider use of implantable rhythm-control devices, such as pacemakers and cardioverter defibrillators, has shown that a significantly greater proportion of patients has silent AF than was previously thought. About 50–60% of patients may have unsuspected episodes of the arrhythmia, almost half of which last >48 hours [165]. The use of implanted monitors, ECG garments, or patient-operated ECG systems may allow expansion of the monitoring period for suspected AF [8].

Clinical history

A complete diagnosis of AF includes analysis of associated medical conditions (see Predisposing clinical conditions, p.1073) and stroke risk factors. This will guide arrhythmia therapy as well as antithrombotic treatment. In addition, the clinician should assess bleeding risk if antithrombotic treatment is indicated. In symptomatic patients, vagal, adrenergic, and other potential trigger mechanisms should be considered. AF should be classified as first onset, paroxysmal, persistent, or permanent ( Fig. 29.4). AF may be symptomatic and asymptomatic in the same patient at different imes [163]. Symptoms may relate to the arrhythmia itself, or to the complications of AF, or the associated medical condition.

Vagal AF [166] is a paroxysmal arrhythmia that usually occurs in the evening, at night, or during weekends, particularly after heavy meals and possibly alcohol consumption. Usually sinus bradycardia or sinus pauses precede the development of the AF and during the AF the heart rate is relatively slow.

Adrenergic AF, on the other hand, is less common, occurs during the day and is provoked by physical or mental stress, and may sometimes be triggered by a stress test. An acceleration of sinus rhythm usually anticipates the arrhythmia and the ventricular rate during the AF tends to be rapid. Some patients have both autonomic forms of AF and many paroxysms are not classically one or the other.

Physical examination

AF presents with an irregular pulse, irregular jugular venous pulsations, and variations in the loudness of the first heart sound and in systolic blood pressure. There may be a deficit between number of heart beats and number of peripheral pulsations, especially when the ventricular rate is rapid. Signs of valvular heart disease, ventricular dilatation, and heart failure may be found.

Investigations

The 12-lead ECG ( Chapter 2) should, in addition to the detection of AF, also be screened for signs of acute myocardial infarction and other signs for structural heart disease (e.g. prior myocardial infarction, LV hypertrophy, bundle branch block or ventricular pre-excitation, signs of cardiomyopathy or ischaemia). In sinus rhythm LA conduction delay is often present, and rare cardiac abnormalities may occasionally be found (29.4).

The ECG may also show other abnormal sinus node function, atrial arrhythmias ( Fig. 29.15A–C) that may trigger AF, or ventricular arrhythmias that may be a sign of heart disease. It is always important to distinguish aberrant conduction from VTs, especially when using antiarrhythmic drugs ( Fig. 29.16).

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Figure 29.16

Holter strip of modified leads V1, V5, and aVF showing atrial fibrillation initiated by the second atrial premature beat (arrows) with left and right aberrant conduction in a patient treated with sotalol for paroxysmal atrial fibrillation. Note the long–short RR sequence at initiation of aberrant conduction. Sotalol may have enhanced onset of aberrancy in this case due to prolongation of refractoriness in the Purkinje system.

The chest radiograph may help to reveal cardiac enlargement ( Fig. 29.8) but is most helpful in detecting intrinsic pulmonary disease and abnormalities of the pulmonary vasculature as in heart failure and pulmonary hypertension.

Echocardiography should be performed at least once in all AF patients. It is indispensable for the management of AF-associated medical conditions. In addition, markers of thrombosis (spontaneous echo contrast) or even a thrombus may be found. Risk markers for stroke include LV hypertrophy or dysfunction, LA enlargement, and low-flow velocities in the LA appendage (LAA). Also, aortic plaques are associated with a high stroke risk. New technical developments have improved the performance of transthoracic echocardiography but for detection of thrombi (e.g. for echo-guided cardioversion) transoesophageal echocardiography is the current standard [1] ( Fig. 29.17; 29.5).

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Figure 29.17

Transoesophageal echocardiogram. This demonstrates a ball thrombus (arrow) in the mouth of the left atrial appendage (dotted line). (Courtesy of Dr Andreas Göette, University Hospital Magdeburg, Germany.)

Laboratory evaluation may be limited to thyroid function tests, serum electrolytes, haemoglobin levels, a serum creatinine measurement, analysis for proteinuria, and a test for diabetes mellitus (usually a fasting glucose measurement). Markers of heart failure (BNP) or inflammation (CRP) or infection may be useful. Thyroid and hepatic function should be assessed when treating patients with amiodarone.

Holter monitoring or event recorders may be used in order to establish the diagnosis of AF. In patients with an implanted device (pacemaker, implantable cardioverter defibrillator, or implantable loop recorder) the logging functions in the device may be very helpful. If patients remain symptomatic with palpitations or reduced exercise tolerance despite normal resting heart rate, the adequacy of rate control may be checked with Holter (or exercise testing in fit patients). AF may start during sinus bradycardia or tachycardia, with single or bouts of atrial ectopic beats, while the start of AF with a supraventricular tachycardia or transitions between AF and atrial flutter may also be seen. Identification of these initiating mechanisms may guide treatment, e.g. vagolytic or beta-blocking agents, atrial pacing or catheter ablation of focal AF or other initiating arrhythmias (see Pacemaker and defibrillator therapy, p.1115). Although the AF burden (total duration or percentage of time in AF) can be measured, its clinical relevance is uncertain.

Exercise testing is useful in patients with permanent AF who remain symptomatic despite adequate rate control at rest. The test may reveal an excessive heart rate rise during the lower stages of exercise, thereby limiting exercise tolerance due to dyspnoea, fatigue, or palpitations. In these cases, rate-control drugs may be targeted to the heart rate during a lower level of exercise. Exercise testing may be useful in detecting ischaemic heart disease, which has consequences for antiarrhythmic treatment of AF. Finally, exercise testing may be used to evaluate the safety of antiarrhythmic drug treatment, e.g. for detecting excessive QRS widening on class IC drugs.

Electrophysiological evaluation may be needed in selected cases, especially in patients in whom other arrhythmias, sick sinus syndrome, or a focal origin is suspected. Many of these patients may receive catheter ablation or a pacemaker.

Embolic targets

An embolus originating from a fibrillating LA may follow the bloodstream to any part of the body. However, the incidence of stroke and of a clinically evident systemic embolism in non-valvular AF differs markedly from the proportion of blood flowing to the brain and to the rest of the body. Thus, the stroke rate is ten times higher than the rate of systemic embolism in patients with non-valvular AF who have not received any anti-thrombotic treatment. In one study of patients with non-valvular AF with incident peripheral embolism, small emboli are more likely to lodge in the cerebral circulation as a result of hydrodynamic, anatomic, and physical factors related to AF [183]. However, advanced age, atrial enlargement and other comorbidities may result in the formation of ‘larger thrombi’ per se which may bypass the carotid orifice merely as a function of size. Of note, ‘silent’ embolism is likely to be more common in the systemic circulation, although this may also occur in cerebral vessels [79, 184].

Anticoagulation therapy versus control

The possible benefit of prophylactic VKA therapy in non-valvular AF has been explored in several randomized controlled studies. The first to be published was the Danish Atrial Fibrillation, ASpirin, AntiKoagulation (AFASAK) study, illustrating a 54% relative risk reduction of stroke associated with a VKA regimen [188]. Since then, other randomized controlled studies exploring the role of VKA as stroke prevention in non-valvular AF have been published.

When pooled together in a meta-analysis, the relative risk reduction was highly significant and amounted to 64%, corresponding to an absolute annual risk reduction

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Figure 29.19

Meta-analysis of ischaemic stroke/systemic embolism with adjusted-dose oral anticoagulation in atrial fibrillation. Reproduced from Lip GYH, Edwards SJ. Stroke prevention with aspirin, warfarin and xilmelagatran in patients with non-valvular atrial fibrillation: a systematic review and meta-analysis. Thromb Res 2006; 118: 321–33.

It is important to note that these studies generally excluded patients with low risk of embolism or markedly increased bleeding risk as well as those with the highest risk of embolism. The latter category, in which VKA treatment is strongly advised (although its benefit has not been illustrated in randomized clinical trials), includes patients who in addition to AF have a prosthetic valve, or suffer from rheumatic mitral valve disease or hypertrophic cardiomyopathy. In addition, AF in the setting of hyperthyroidism is often placed in this category, although the evidence for high stroke risk is weak.

Supported by the results of the trials cited above, VKA treatment is strongly recommended for patients with AF with ‘definitive’ or two or more ‘combination’ stroke risk indicators provided there are no contraindications.

Antiplatelet therapy versus control

Eight independent randomized controlled studies, together including 4876 patients, have explored the prophylactic effects of antiplatelet therapy, most commonly acetylsalicylic acid (ASA), compared with placebo on the risk of thromboembolism in patients with AF [189]. When aspirin alone was compared to placebo or no treatment in seven trials, meta-analysis showed that aspirin was associated with a non-significant 19% (CI, -1% to 35%) reduced incidence of stroke. There was an absolute risk reduction of 0.8% per year for primary prevention trials and 2.5% per year for secondary prevention [189]. When all randomized data from all comparisons of antiplatelet agents and placebo or control groups were included in the meta-analysis, antiplatelet therapy reduced stroke by 22%.

Of note, the dose of aspirin differed markedly between the studies, ranging from 50–1300mg daily. Furthermore, much of the beneficial effect of aspirin was driven by the results of the SPAF-I clinical trial, which suggested a 42% stroke risk reduction with aspirin versus placebo [190]. In this trial, there were inconsistencies for the aspirin effect in this trial between the results for the warfarin-eligible (relative risk reduction, 94%) and warfarin-ineligible (relative risk reduction, 8%) arms. Also, aspirin has less effect in people older than 75 years and did not prevent severe or recurrent strokes. The magnitude of stroke reduction of aspirin versus placebo is comparable to that seen if aspirin were given for vascular disease subjects—given that AF commonly coexists with vascular disease, the modest benefit seen for aspirin in AF is likely to be related to the effects on vascular disease.

Anticoagulant therapy versus antiplatelet therapy

Direct comparison between the effects of VKA and ASA has been undertaken in nine studies, illustrating that VKA was significantly superior with a relative risk reduction of 39% [189]. The latter relative risk reduction has largely been driven by the BAFTA trial, which showed that warfarin (target INR 2–3) was superior to aspirin 75mg in reducing the primary endpoint of fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant arterial embolism by 52%, with no difference in risk of major haemorrhage between warfarin and aspirin ( Fig. 29.20) [186].

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Figure 29.20

Warfarin versus aspirin for stroke prevention in an elderly community population with AF: the Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA). Modified from Mant J, Hobbs FD, Fletcher K, et al.; BAFTA investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007; 370: 493–503.

When the trials prior to BAFTA were considered, the risk for intracranial haemorrhage was doubled with adjusted-dose warfarin compared with aspirin, although the absolute risk increase was small (0.2% per year) [189].

Combination therapies

Several attempts have been made to combine drugs with different antithromboembolic mechanisms, mostly low-dose VKA treatment with an antiplatelet drug. No study has shown any superior outcome for such a drug combination compared with dose-adjusted VKA only in preventing stroke or embolism in non-valvular AF.

Antiplatelet therapy has also been combined with therapeutic anticoagulation in AF cohorts, and these have shown a high rate of bleeding in the combination treatment arm [191, 192]. An ancillary analysis from the SPORTIF (Stroke Prevention using an Oral Thrombin Inhibitor in Atrial Fibrillation) trials, which compared aspirin users with non-users [192] found no additive effect of taking aspirin for stroke prevention or a reduction in vascular events (including death or myocardial infarction) in patients who were given anticoagulation (warfarin or ximelagatran); instead, aspirin use resulted in a substantial increase in risk of bleeding.

There is no role for the routine addition of aspirin to anticoagulation therapy in AF patients with stable vascular disease, given the lack of benefit in reducing vascular events, and the significant increase in bleeding risks [193].

Other antithrombotic agents

Clopidogrel, in combination with aspirin, has been compared against warfarin in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W) trial. This trial was stopped early due to the inferiority of aspirin–clopidogrel combination therapy against warfarin for stroke prevention, with no difference in bleeding events between the treatment arms ( Fig. 29.21) [194]. An ancillary analysis of AF subjects participating in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial of patients with stable cardiovascular disease or multiple cardiovascular risk factors, which compared combination aspirin–clopidogrel therapy to aspirin alone, found no benefit of combination therapy but an excess of severe or fatal extra-cranial haemorrhage with combination therapy [195].The recent ACTIVE-A trial tested the hypothesis that the addition of clopidogrel 75mg to aspirin would reduce the risk of vascular events in 7554 patients with AF [196]. At a median of 3.6 years of follow-up, major vascular events were reduced in patients receiving aspirin–clopidogrel (6.8%/year vs. aspirin alone, 7.6%/year: RR 0.89; 95% CI 0.81–0.98; P = 0.01). This difference was primarily due to a reduction in the rate of stroke with combination therapy (2.4%/year vs. 3.3%/year: RR 0.72; 95% CI, 0.62–0.83; P <0.001). However, major bleeding increased with combination therapy (2.0%/year vs. 1.3%/year. RR 1.57; 95% CI, 1.29–1.92; P <0.001). Thus, in AF patients for whom VKA therapy was unsuitable, the addition of aspirin–clopidogrel reduced the risk of major vascular events, especially stroke, but increased the risk of major haemorrhage. Nonetheless, 50% of subjects entered the trial due to 'physician perception of being unsuitable for VKA therapy' and 23% had a relative risk factor for bleeding at trial entry. However, of patients perceived not to be candidates for VKA therapy, only a small proportion still have the same relative contraindication to VKA a year later. Hence aspirin–clopidogrel therapy could be considered as an interim measure pending use of more effective thromboproplylaxis with VKA. Other antiplatelet agents such as indobufen and triflusal have been investigated in AF, with the suggestion of some benefit, but more data are required before definitive conclusions can be made [167].

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Figure 29.21

Primary endpoint (stroke, systemic embolus, myocardial infarction and vascular death in the ACTIVE W Study comparing oral anticoagulation with warfarin against a fixed dose of clopidogrel and aspirin (A). The occurrence of major bleeding (B). ASA, aspirin; OAC, oral anticoagulation. Modified with permission from Connolly S, Pogue J, Hart R, et al.; ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903–12.

Investigational drugs

Several new anticoagulant drugs—broadly in two classes, the oral direct thrombin inhibitors (DTI) and the oral factor Xa inhibitors (FXaI)—have been developed as possible alternatives to VKA ( Fig. 29.22) [197]. The first oral DTI, ximelagatran was tested in two large-scale clinical studies, and was found to be as effective as adjusted-dose warfarin in the prevention of ischaemic strokes or systemic emboli (RR 1.04; 95% CI: 0.77–1.40) ( Fig. 29.19) with less risk of major bleeding (RR, 0.74; 95% CI, 0.56–0.96) [198]. Further development of ximelagatran has been discontinued due to liver toxicity.

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Figure 29.22

Simplified coagulation cascade and sites of action of new anticoagulant agents. Modified with permission from Turpie AG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008; 29: 155–65.

Other DTIs (e.g. dabigatran and AZD0837), as well as Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, YM150, etc.) and non-warfarin vitamin K antagonists (ATI-5923) are being developed for stroke prevention in AF [199]. The possible benefit of these drugs awaits the outcomes of clinical studies.

One indirect FXaI, idraparinux, which requires once-weekly administration, was tested against warfarin in one trial [200]. This found that idraparinux was non-inferior to warfarin for stroke prevention, but there was a marked excess of bleeding with idraparinux compared to warfarin. A biotinylated version of idraparinux is undergoing a clinical trial in AF, with the potential of anticoagulant reversal should bleeding occur.

Optimal INR

Currently, the level of anticoagulation in a serum sample is expressed as the INR, which is the ratio between the actual prothrombin time and that of a standardized control serum. Although arguments have been raised against the accuracy of this comparative technique [201], it has become widely accepted.

Based on the pooled information from achieving a balance between stroke risk with low INRs and an increasing bleeding risk with high INRs [202, 203], a consensus has been reached that an INR of 2.0–3.0 is the likely optimal range for prevention of stroke and systemic embolism in patients with non-valvular AF. A mortality risk analysis in a VKA-treated population comprising >40,000 patients suggests that the target INR window should be narrower, with a target value close to 2.2–2.3 [204]. Fig. 29.23 illustrates the risk of ischaemic stroke and intracranial bleeding relative to the INR level as well as the 1-month mortality risk in relation to INR in patients with AF.

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Figure 29.23

(A) Adjusted odds ratio for ischaemic stroke and intracranial bleeding in relation to international normalized ratio (INR). Reproduced with permission from Odén A, Fahlén M. Oral anticoagulation and risk of death: medical record linkage study. Br Med J 2002; 325: 1073–5. (B) Risk of death during the month following an INR test in relation to the INR value. The blue line represents the mortality risk for a 71-year-old woman. The horizontal dotted red line represents the mortality risk for the entire population of 71-year-old females.

Keeping within a target INR of 2–3 is difficult. One of the many problems with anticoagulation with VKA is the high inter- and intra-individual variation in INRs. VKAs also have significant drug, food, and alcohol interactions. Patients stay within target INR range (2–3) for 60–65% of the time [205], but many ‘real life’ studies even suggest that this figure may be <50%.

The elderly may pose a particular problem. One hospital-based cohort suggested a high bleeding rate in elderly subjects (>80 years old) initiated on warfarin, especially in the first 3 months following the start of warfarin [206]. In this study, increasing stroke risk was associated with an increasing risk of bleeding, which in turn led to more discontinuations. Whilst a lower target INR range (1.8–2.5) has been proposed for the elderly, this is not based on any trial evidence, and cohort studies even suggest a twofold increase in stroke risk at INR 1.5–2.0 [207], and is therefore not recommended. Also, the BAFTA trial shows the benefit of conventional dose warfarin over aspirin in the elderly (aged ≥75 years), irrespective of age categories [186].

In addition to the fear of drug-induced bleeding complications, VKA treatment is associated with several other reasons that contribute to its underuse in patients with non-valvular AF [208]. In short, the barriers to the use of VKA treatment in non-valvular AF patients may relate to the doctor as well as the patient and the healthcare system. In addition, many patients with AF have limited understanding of the disease process as well as the need for anticoagulation therapy to prevent thromboembolism [209].

The maintenance, safety, and effectiveness of INR within range can be influenced by pharmacogenetics of VKA therapy, particularly the cytochrome P450 2C9 gene (CYP2C9) and the vitamin K epoxide reductase complex 1 gene (VKORC1). CYP2C9 and VKORC1 genotypes can influence warfarin dose requirements, whilst CYP2C9 variant genotypes are associated with bleeding events [210]. The ability to determine mutations in the genes coding for these two proteins could influence future VKA dosing patterns (i.e. genotype-guided therapy), but just how much would these would really add to regular, conscientious monitoring of the INR and dose adjustment is undetermined. Ongoing trials are addressing this question.

Anticoagulation near-patient testing and self-monitoring

The need for regular monitoring of oral anticoagulation therapy has led to a substantial increased use of ‘point of care’ or ‘near patient’ testing schemes, as well as patient self-monitoring approaches ( Fig. 29.24).

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Figure 29.24

Self-testing device for assessment of international normalized ratio (INR) (CoaguChek XS® Plus system—PT/INR monitoring).

Thus, patients may have anticoagulation-monitoring testing at a local clinic (e.g. general practitioner clinic using an INR testing machine, or blood sample taken at a local clinic which is batched and sent to a central laboratory) and the INR result phoned to the patient, with VKA dose change, if necessary. Alternatively home monitoring can be performed using a personal INR testing machine allowing patients to alter the warfarin dose themselves [211].

Self-monitoring could be considered if the patient is physically and cognitively able to perform the self-monitoring test [212, 213] or a designated carer may be used. Appropriate training by a competent healthcare professional is needed and the patient must remain in contact with a named clinician.

Paroxysmal atrial fibrillation

The stroke and thromboembolic risk in paroxysmal AF is less well defined, and such patients have represented the minority (usually <30%) in the clinical trials of thromboprophylaxis. A recent large trial programme did not identify a difference in stroke risk between paroxysmal or chronic forms of AF [77].

A retrospective hospital record study followed >400 individuals with paroxysmal AF for >25 years [214]. In these non-VKA taking patients, there was a clustering of thromboembolism at the time of onset of paroxysmal AF, namely 6.8% during 1 month. Later, the annual embolic rate varied from 0.6–2.6%. Following transition to permanent AF, which occurred in every third patient, the rate of embolism rose to a significantly higher level. Some of the observed differences in thromboembolic rates are clearly attributable to the presence or absence of stroke risk factors.

Another study, exploring the embolic risk factors in >700 patients with paroxysmal AF, verified a 2.2% annual rate of embolism, typically occurring in males above the age of 65 [77]. Importantly, individuals without any underlying disorder had a low embolic event rate (0.7% per year). Data from the non-VKA arms of clinical trials show that stroke risk in paroxysmal AF was comparable to that seen in permanent AF, and is dependent upon the presence of stroke risk factors [171, 215]. Thus, current guidelines suggest that prevention of thromboembolism is appropriate in patients with paroxysmal AF [1].

Perioperative anticoagulation

Patients with AF who are anticoagulated will require temporary interruption of a VKA before surgery or an invasive procedure. Many surgeons require an INR of <1.5 or even INR normalization before undertaking surgery. Thus, VKAs should be stopped approximately 5 days before surgery, to allow the INR to fall appropriately. VKA should be resumed at the ‘usual’ maintenance dose (without a loading dose) on the evening of (or the next morning) after surgery assuming there is adequate haemostasis. If surgery is urgent but the INR is still elevated (>1.5), the administration of low-dose oral vitamin K (1–2mg) to normalize the INR may be considered.

In patients with a mechanical heart valve or AF at high risk for thromboembolism, management can be problematic. Such patients should be considered for ‘bridging’ anticoagulation with therapeutic doses of heparin (either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH)) during the temporary interruption of VKA therapy [216].

Atrial fibrillation presenting with acute coronary syndrome and/or percutaneous coronary intervention with stenting

Increasing numbers of patients with AF may present with an acute coronary syndrome (ACS). Given that AF is also associated with CAD, some AF patients would require percutaneous coronary intervention, with the possibility of stent implantation. Current guidelines for ACS and/or PCI recommend the use of aspirin–clopidogrel combination therapy after ACS (9–12 months), and after a stent (4 weeks for a bare metal stent, 6 or more months for a drug-eluting stent).

However, there are limited data to guide the optimal antithrombotic regimen to use in anticoagulated patients with AF, given that bleeding with triple therapy (VKA, aspirin, and clopidogrel) may be substantial. The largest published cohort [217] suggests that non-VKA use was associated with an increase in mortality and major adverse cardiac events, with no significant difference in bleeding rates between VKA and non-VKA users.

Current consensus guidelines suggest that drug-eluting stents should be avoided and triple therapy (VKA, aspirin, clopidogrel) used in the short term, followed by more long-term therapy with VKA plus a single antiplatelet drug [218, 219].

Atrial fibrillation patients presenting with an acute stroke

Acute stroke is a common first presentation of a patient with AF, given that the arrhythmia often develops asymptomatically. There are limited trial data to guide our management, and there is concern that patients within the first 2 weeks of having had a cardioembolic stroke are at greatest risk of having stroke recurrence because of further thromboembolism. However, anticoagulation in the acute phase may result in intracranial haemorrhage or haemorrhagic transformation of the infarct. In most stroke survivors with AF it is reasonable to initiate anticoagulation at approximately 2 weeks after the stroke in patients with minor strokes or TIA, anticoagulation could be initiated earlier, after cerebral imaging as excluded any intracranial bleeding.

Atrial flutter

Large-scale prospective observational or interventional studies on the stroke rate in atrial flutter per se are lacking. However, the risk of stroke linked to atrial flutter has been studied retrospectively in a large number of older patients, and was similar to that seen in AF [219]. Thus, thromboprophylaxis in a patient with atrial flutter should follow the same guidelines as if the patient had AF [185].

Pregnancy

On occasion, AF may occur in pregnant women, especially in relation to valvular heart disease, prosthetic heart valves, or venous thromboembolism. A thorough discussion of the potential risks and benefits of any anticoagulation regimen is needed with the patient, and a close liaison on management between the cardiologist and obstetrician is mandatory.

VKAs can be teratogenic and in many cases should be substituted with UFH or LMWH for the first trimester of the pregnancy [221]. Pregnant patients with AF and mechanical prosthetic valves who elect to stop warfarin between weeks 6 and 12 of gestation should receive continuous intravenous UFH, dose-adjusted UFH, or dose-adjusted subcutaneous LMWH [222] and may start VKA in the second trimester at an only slightly elevated teratogenic risk. For pregnant women with acute venous thromboembolism, subcutaneous LMWH or UFH should be continued throughout pregnancy and anticoagulant prophylaxis continued for at least 6 weeks postpartum [221].

Silent stroke

A history of previous stroke or TIA is the most powerful risk factor for a recurrent cerebrovascular event. As stroke in patients with AF is primarily embolic, the detection of asymptomatic cerebral emboli may identify high-risk patients. The prevalence of silent cerebral infarct on computer tomography images of the brain in AF patients without neurological deficit ranged from 15–26% in the SPINAF and SPAF (Stroke Prevention Atrial Fibrillation) studies [228, 229]. These silent strokes may contribute to impaired cognitive function in AF patients.

Transcranial Doppler ultrasound may identify asymptomatic patients with an active embolic source or patients with prior stroke who are at high risk of recurrent stroke. During 1-hour bilateral Doppler monitoring from the middle cerebral arteries, the frequency of embolization was 13% in patients with previous AF-related stroke or TIA and 16% in those individuals without a history of a cerebrovascular event [230]. The incidence of embolic signals was higher in untreated patients compared with those receiving warfarin (11.9% vs. 1.5%) [231].

Rhythm- versus rate-control studies

Several randomized studies directly and prospectively compared the effect of rate and rhythm control on patient outcomes ( Table 29.8). The major studies were the Atrial Fibrillation Follow up Investigation of Rhythm Management (AFFIRM) trial [237], the RAte Control versus Electrical Cardioversion (RACE) trial [238], and the Atrial Fibrillation Congestive Heart Failure (AF-CHF) trial [239]. There were also a series of pilot studies performed, including the Pharmacological Intervention in Atrial Fibrillation (PIAF) [240], Strategies of Treatment of Atrial Fibrillation (STAF) [241], and How to Treat Chronic Atrial Fibrillation (HOT CAFÉ) [242] among others. Virtually all studies have shown that primary rate control is not inferior to rhythm control. Meta-analysis has demonstrated no significant excess or reduced mortality with either strategy [243].

The AF-CHF trial compared rate- and rhythm-control strategies specifically in patients with an ejection fraction of 35% or less and NYHA II–IV heart failure ( Fig. 29.27) [239]. The study showed no benefit from rhythm control (mainly with amiodarone) on top of optimal medical therapy on cardiovascular death (the primary outcome) as well as pre-specified secondary outcomes (total mortality, worsening heart failure, stroke, and hospitalization). Cardiovascular death occurred in 26.7% of the patients in the rhythm-control group compared with 25.2% in the rate-control arm.

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Figure 29.27

All-cause mortality in the rate control and rhythm control arms of the AFFIRM study (A). Cardiovascular mortality in the rate-control and rhythm-control arms of the AF-CHF study (B). In the AFFIRM study, more deaths occurred in the rhythm-control arm (356/2027 (26.7%)) than in the rate-control arm (310/2027 (25.9%)), but the difference was not statistically significant (hazard ratio, 1.15 (95% CI, 0.99–1.34); p = 0.08). In the AF-CHF study, 182 of 682 patients (27%) in the rhythm-control group died from cardiovascular causes compared with 175 of 694 patients (25%) in the rate-control group (hazard ratio, 1.06; 95% CI, 0.86–1.30). AFFIRM, Atrial Fibrillation Follow-up Investigation of Rhythm Management; AF CHF, Atrial Fibrillation in Congestive Heart Failure. Reproduced with permission from Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347: 1825–33; and Roy D, Talajic M, Nattel S, et al. for the Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008; 358: 2667–77.

Indications for rhythm versus rate control

Rate control as a primary strategy is now accepted in older, sedentary, and asymptomatic (or only mildly symptomatic) patients (EHRA I–II) who have had their arrhythmia for many years, without significant impairment of ventricular function and exercise tolerance. Following the AF-CHF study, rate control is a legitimate primary treatment option for patients with heart failure who can tolerate AF without worsening NYHA functional class. Rhythm control with antiarrhythmic drugs, cardioversion, or ablation remains treatment of choice in patients who are symptomatic, in patients with recent onset AF, or in young and active individuals.

On-treatment analysis of outcomes in the AFFIRM trial has shown a 47% reduction in the risk of all-cause death if sinus rhythm was maintained irrespective of the treatment strategy [244]. If safer and more effective antiarrhythmic agents were available, sinus rhythm might confer a favourable outcome and many new antiarrhythmic agents are under investigation ( Fig. 29.28) [107].

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Figure 29.28

Antiarrhythmic agents for atrial fibrillation. *Azimilide is not used for treatment of atrial fibrillation; its use in patients with implantable defibrillators is under consideration. **Nifekalant is used in Japan, mainly for termination of ventricular tachycardia. ACEIs, angiotensin converting enzyme inhibitors; ARBs angiotensin type I receptor blockers; ARDAs, atrial repolarization delaying agents; HT, hydroxytryptamine; PUFA, polyunsaturated fatty acids; RyR, ryanodine receptors; SAC, stretch-activated channels. Reproduced with permission from Savelieva I, Camm J. Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches. Europace 2008; 10: 647–65.

Where to initiate antiarrhythmic drug therapy

Where to initiate antiarrhythmic drug therapy must take into account risk and practicality. Patients at anticipated high risk of developing adverse effects (e.g. patients with an inherently prolonged QT interval, or patients at risk of tachycardia–bradycardia syndrome upon termination of AF), should not be prescribed antiarrhythmic drugs outside the hospital setting. For some antiarrhythmic agents, e.g. dofetilide, there is formal requirement for in-hospital initiation.

In the absence of proarrhythmia concerns and formal labelling, convenience and cost effectiveness favour out-of-hospital initiation, e.g. oral propafenone and flecainide (usually in combination with AV blocking drugs to prevent fast ventricular rates if atrial flutter occurs) in patients with lone AF or AF associated with hypertension without significant LV hypertrophy. Amiodarone can be safely started on an outpatient basis, given its long elimination half-life period and low probability of developing torsade de pointes. An ECG control and/or trans-telephonic ECG monitoring should be arranged to provide surveillance of heart rate, PR and QT interval durations (sotalol, amiodarone, dofetilide), QRS width (flecainide, propafenone), and assessment of the efficacy of treatment. When sotalol therapy is initiated outside hospital, the initial dose should be low and up-titration should depend on the heart rate and QT interval.

‘Pill in the pocket’ approach

In patients with no or minimal structural heart disease and relatively infrequent (less than monthly), symptomatic paroxysms of AF of distinct onset which do not cause significant haemodynamic compromise (e.g. hypotension), a single loading dose of propafenone or flecainide can be used for expedient cardioversion [248]. In a proof of concept study, patients with paroxysmal AF, who had been successfully treated in hospital with either oral flecainide or propafenone, were instructed to take a single oral dose of the relevant drug within 5min of noticing palpitations. This ‘pill in the pocket’ strategy resulted in the reduction in the number of visits and hospitalizations, despite the same frequency of arrhythmia episodes [249].

The experience with this approach is limited and neither drug is licensed for patients to use for self-treating single attacks. As there is a danger of developing atrial flutter with 1:1 AV conduction, QRS widening, and rarely LV dysfunction, it is mandatory that the efficacy and safety of this strategy is first tested in-hospital. Furthermore, it is advisable to combine these agents with an AV-nodal slowing drug, e.g. a beta-receptor blocker, verapamil, or diltiazem. Atrial flutter was reported in 5–7% of patients who received oral loading doses of propafenone or flecainide for conversion of AF [250].

Drugs for cardioversion of atrial fibrillation

Intravenous propafenone and flecainide are very effective in cardioversion of AF of <72 hours’ duration, with conversion rates as high as 80–90% within an hour after the start of infusion [251–253]. When taken orally as a loading dose (450–600mg for propafenone, 200–300mg for flecainide), restoration of sinus rhythm is more delayed, but conversion rates (70–80% at 8 hours) are comparable to those observed after intravenous administration [250, 254–259]. The drugs are less effective for termination of AF lasting >7 days.

Class IC drugs are ineffective for conversion of atrial flutter. They slow conduction within the re-entrant circuit and prolong the atrial flutter cycle length, but rarely interrupt the circuit. The efficacy rates have been reported to be as low as 13–40% [260].

Ibutilide is moderately effective for cardioversion of AF and is more effective for cardioversion of atrial flutter (31–44% vs. 56–70%) [261, 262]. The drug is available only as an intravenous formulation and is usually administered as a 1-mg bolus over 10min. Higher doses of ibutilide such as a single bolus of 2mg or two successive infusions of 1mg may be required for cardioversion of AF [261, 263, 264]. The antiarrhythmic effect of ibutilide decreases if the arrhythmia had persisted for >7 days.

Ibutilide prolongs the QT interval and may induce ventricular proarrhythmia. In the ibutilide trials, the incidence of polymorphic VT or torsade de pointes requiring electrical cardioversion was 0.5–1.7% and the incidence of self-terminating polymorphic VT was 2.6–6.7% [262, 265]. There are insufficient data to support the use of ibutilide in patients with significant structural heart disease as many controlled studies of ibutilide have only enrolled patients with mild or moderate underlying heart disease.

Oral dofetilide has been studied extensively and is considered safe and relatively effective for pharmacological cardioversion of AF including arrhythmia duration of >7 days. Two medium-size prospective studies, SAFIRE-D (Symptomatic Atrial Fibrillation Investigative Research on Dofetilide) and EMERALD (European and Australian Multicenter Evaluative Research on Dofetilide) reported a modest 30% cardioversion rate of persistent AF with high-dose (1000mcg twice daily) oral dofetilide compared with 1.2% of spontaneous conversion on placebo [266] and 5% on sotalol [267].

In the pooled analysis from the DIAMOND (Danish Investigations of Arrhythmia and Mortality ON Dofetilide) studies in patients with symptomatic heart failure (DIAMOND-CHF) or myocardial infarction with LV dysfunction (DIAMOND-MI), oral dofetilide had a neutral effect on mortality and also demonstrated a greater rate of conversion to sinus rhythm (44% vs. 14%) [236].

Dofetilide causes QT interval prolongation and a non-negligent risk of torsade de pointes. The effect on the QT interval is dose-related and proarrhythmia typically occurs within the first 2–3 days after initiation of therapy. Therefore, it is mandatory that dofetilide be initiated in-hospital and that patients should be monitored for at least 3 days. In addition, the dose of dofetilide requires adjustment to creatinine clearance ( Table 29.9).

Intravenous sotalol (1–1.5mg/kg) is ineffective for acute pharmacological cardioversion of AF: the conversion rates at 10–20% were not different from placebo [261, 262, 268, 269]. The antifibrillatory effect of sotalol is limited by reverse use dependency of its effect on atrial refractoriness: sotalol prolongs the atrial effective refractory period at normal and slow atrial rates, but not during rapid AF.

There is evidence that oral sotalol may offer a modest benefit of facilitating conversion to sinus rhythm and, in addition, can ensure ventricular rate control in patients awaiting electrical cardioversion. In the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T), 24.2% of patients with persistent AF treated with sotalol converted to sinus rhythm within 28 days, compared with 27.1% on amiodarone and only 0.8% on placebo [19].

The adverse effects of sotalol include hypotension, bradycardia, QT interval prolongation, and associated ventricular proarrhythmia (torsade de pointes). Bradycardia and hypotension were the commonest with intravenous sotalol [19]. The risk of proarrhythmia is increased in the presence of LV hypertrophy and in renal failure and the drug is contraindicated in these conditions.

Amiodarone is considered a relatively safe drug for acute pharmacological cardioversion and is the drug of choice in patients with advanced underlying heart disease. Amiodarone does not have any negative inotropic effect, controls the ventricular rate, and is associated with a low incidence of torsade de pointes. In meta-analysis of 13 randomized controlled studies in 1174 patients, the placebo-subtracted efficacy of amiodarone was 44%, but its effect was delayed up to 24 hours [270]. Intravenous amiodarone followed by an oral maintenance dose increases the likelihood of conversion to sinus rhythm [271].

The mortality and morbidity study CHF-STAT (Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy) in patients with a mean ejection fraction of 25% has shown that long-term treatment with oral amiodarone 400mg daily for the first year and 300mg daily for the remainder of the 4.5-year trial was associated with greater rates of conversion to sinus rhythm compared with placebo (31% vs. 7.7%) [272].

Unlike propafenone and flecainide, amiodarone preserves its efficacy in patients with long-standing AF. Thus, in patients with a mean AF of almost 2 years, amiodarone 600mg daily for 4 weeks restored sinus rhythm in 34% of patients compared with 0% in the placebo group [273].

Amiodarone prolongs the QT interval, but, unlike pure class III agents, exhibits a low arrhythmogenic potential (<1%) [274]. The most common adverse effects of intravenous amiodarone are hypotension and relative bradycardia.

Class IA drugs procainamide (oral and intravenous) and quinidine (oral) have been widely used for cardioversion of AF. In direct comparisons, the efficacy of intravenous procainamide 1000–1200mg was comparable to that of propafenone (69.5% vs. 48.7%) [275], flecainide (65% vs. 92%) [276], or amiodarone (68.5% vs. 89.1%) [277] for conversion of AF of <48 hours. Quinidine given orally in a cumulative dose of up to 1200–2400mg over 24 hours has been shown to cardiovert 60–80% of recent onset AF [278, 279].

Because of the non-target effects (vasodilatation, hypotension, anticholinergic action, AV node blockade, worsening heart failure, and in addition to these, gastrointestinal discomfort and a 6% increased risk of torsade associated with quinidine), the drugs are less commonly used for cardioversion of AF.

There is limited evidence for the efficacy of intravenous disopyramide for acute pharmacological cardioversion in patients with AF. In one study, disopyramide administered as a bolus of 2mg/kg over 5min restored sinus rhythm in (71%) patients with self-limiting lone AF and three of seven (43%) patients with atrial flutter [280]. There are concerns, however, that the adverse effects such as proarrhythmia, hypotension, asystole, and non-target effects resulting from anticholinergic activity of disopyramide, may offset its modest antiarrhythmic potential.

Vernakalant is a new antiarrhythmic drug agent [281] with an affinity to ion channels specifically involved in the repolarization processes in atrial tissue, in particular, the ultrarapid potassium repolarization current I_Kur, but has little impact on major currents responsible for ventricular repolarization. It does, however, inhibit the inward sodium current (I_Na) and slows myocardial conduction, especially at high rates.

In the randomized, double-blind, placebo controlled Atrial arrhythmia Conversion Trials (ACT), vernakalant administered as a 10-min infusion of 3mg/kg (followed by a second infusion of 2mg/kg if AF persisted after 15min) was significantly more effective than placebo in converting AF of <7 days (52% compared with 3.6–4%, respectively) [282, 283]. The highest efficacy was observed for AF of up to 72 hours (70–80%). Vernakalant was ineffective in converting AF of >7 days duration and did not convert atrial flutter.

The drug was well tolerated; the most common (>5%) side effects of vernakalant were dysgeusia, sneezing, and nausea. Minor QTc prolongation was reported but there has been little or no proarrhythmia [282, 284].

Magnesium sulphate Meta-analysis of eight studies in 476 patients showed that magnesium sulphate, administered intravenously at an initial dose of 1200–5000mg over 1–30min (in some studies followed by the second dose or continuous infusion for 2–6 hours), was superior to placebo or the active comparator in cardioverting AF with an odds ratio of 1.6 (95% CI, 1.07–2.39) [285]. The most common side effects were sensation of warmth and flushing. Magnesium prolongs the atrial and AV node refractory periods and therefore in addition to its antifibrillatory effect, it may slow the ventricular rate. Magnesium is not routinely used for pharmacological cardioversion of AF, but it may potentiate the effect of other antiarrhythmic agents.

Digitalis, beta-blockers, and calcium antagonists usually are ineffective for acute conversion of AF [286, 287]. Digoxin may even be profibrillatory due to its cholinergic effects which may cause a non-uniform reduction in conduction velocity and effective refractory periods of the atria [288]. Short-acting intravenous beta-blockers (e.g. esmolol) and non-dihydropyridine calcium antagonists (verapamil and diltiazem) are more commonly used for rate control than for restoration of sinus rhythm.

Investigational antiarrhythmic agents

A raft of other amiodarone analogues (e.g. celivarone) and amiodarone-derivative with modified bonds within the molecule is currently at various stages of development ( Fig. 29.28) [107]. An oral formulation of vernakalant 600mg BID has been reported to be useful for prevention of AF recurrence after electrical cardioversion, with a modest superiority to placebo (51% vs. 37%) [107]. There is evidence that an antianginal drug, ranolazine, may also produce an antiarrhythmic effect due to multiple channel blockade, particularly late sodium current blockade.

Acute rate control

The target heart rate for acute rate control is 80–100 beats per minute (bpm) during AF. In patients with rapid ventricular rate, intravenous verapamil, diltiazem, and beta-blockers (usually metoprolol or the rapidly-eliminated esmolol) are commonly used for rapid ventricular rate control ( Table 29.10) [330]. All drugs are equally effective in reducing the ventricular response rate by approximately 20–30% in 20–30min and have a similar risk of adverse effects (usually hypotension and bradycardia; although LV dysfunction and high-degree heart block may occur). Beta-blockers are preferable in patients with a history of myocardial infarction or if thyrotoxicosis is suspected as a cause of the arrhythmia, whereas verapamil and diltiazem are preferred in patients with acutely exacerbated chronic obstructive airways disease.

Intravenous digoxin is no longer the treatment of choice for acute rate control because of delayed onset of its therapeutic effect (>60min). However, because digoxin has a positive inotropic effect, it is a reasonable adjunct to beta-blockers in patients with impaired LV function and moderately fast ventricular rates.

Agents with the primary effect on the AV node should not be used for rate control in patients with known or suspected pre-excitation syndrome: these agents will only affect AV nodal conduction and will have no effect on rapid conduction via the accessory pathway. In patients with accessory pathways, sodium-channel blockers (e.g. intravenous ajmaline or flecainide) can slow anterograde conduction via the accessory pathway.

Intravenous amiodarone can be used for acute ventricular rate control when other agents have no effect on ventricular response or are contraindicated, for example, in haemodynamically unstable AF refractory to electrical cardioversion [331]. The AV blocking effect of amiodarone is complemented by its antifibrillatory action. The disadvantages of intravenous amiodarone are slow onset of action and increased risk of phlebitis. Sotalol can also slow down the ventricular rate due to its beta-blocking properties [332], but its negative inotropic effect in patients with LV dysfunction and risk of torsades due to QT interval prolongation reduce its value as a rate controlling agent.

There is limited evidence of the use of clonidine (due to its central sympatholytic activity) [333] and magnesium [285] for ventricular rate control. In a meta-analysis, intravenous magnesium reduced the ventricular rate to <90–100 within 5–15 min of infusion. Adenosine derivatives with a high specificity for adenosine A1 receptors and longer half-life periods (e.g. tecadenoson, selodenoson, and capadenoson) are currently under investigation [107, 334].

Rate control in paroxysmal and persistent atrial fibrillation

Rate control is an essential constituent of management of AF and is pertinent to all types of the arrhythmia. In paroxysmal and persistent AF, rate control is important during the recurrence or prior to electrical cardioversion. Verapamil, diltiazem, and beta-blockers (metoprolol, atenolol, bisoprolol, carvedilol, and nadolol) are drugs of choice. They are also commonly prescribed in combination with the class IC agents, propafenone and flecainide, to prevent fast ventricular rates due to 1:1 AV conduction when recurrent AF evolves to flutter.

Digoxin has been shown to reduce the ventricular rate during symptomatic paroxysms of AF by approximately 15bpm and has probably rendered some episodes asymptomatic [335], but because of its profibrillatory effect, digoxin usually should be avoided if the arrhythmia is self-terminating or electrical cardioversion is planned and rhythm control is pursued.

Some antiarrhythmic drugs, such as sotalol, amiodarone, and dronedarone, slow AV conduction and thus offer an additional benefit of ventricular rate control during recurrences of AF without significantly affecting the overall exercise capacity [19, 272, 336–338]. However, antiarrhythmic drugs are not likely to be routinely employed for long-term rate control, e.g. in permanent or accepted AF, because of potential proarrhythmic and non-target side effects.

Rate control in permanent atrial fibrillation

Current guidelines define adequate rate control as maintenance of the ventricular rate response between 60–80bpm at rest and 90–115bpm during moderate exercise, but few systematic studies explored the effect of rate slowing drugs on chronotropic competence in AF or defined upper limits of the appropriate ventricular rate response during exercise [339] and no controlled clinical trials have validated these values with regard to their effects on morbidity or mortality. In post hoc pooled analysis of the AFFIRM and RACE studies, patients with mean ventricular rates during AF within the AFFIRM (≤80bpm) or RACE (<100bpm) criteria had a better outcome than patients with ventricular rates ≥100bpm (hazard ratio 0.69 and 0.58, respectively for ≤80 and <100 compared with ≥100bpm) [340].

Although rapid ventricular rates can be detrimental, too slow heart rate can be problematic, particularly in patients with impaired diastolic filling, hypertension, and LV hypertrophy when loss of atrial contraction may cause a marked decrease in cardiac output. Furthermore, rhythm irregularity per se may contribute to ventricular dysfunction [341].

Ventricular rate control at rest does not always translate into effective control during exercise. Ambulatory 24-hour ECG monitoring is considered sufficient for assessment of rate control in elderly and sedentary individuals, whereas in younger individuals, an exercise stress test may be necessary ( Figs. 29.34 and 29.35). RACE II was instigated to assess whether maintaining strict rate control, i.e. mean resting heart rate <80bpm and heart rate during mild exercise <110bpm, can offer any additional benefit to standard practice [342].

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Figure 29.34

ECG strips recorded before (A) and after (B) exercise stress test in a young patient with atrial fibrillation and controlled ventricular rates at rest. Note a sharp increase in ventricular rates showing inadequate ventricular rate control after just 1.5min of exercise prompting early termination of the test (C).

Drugs for rate control. Digoxin, beta-blockers, verapamil, and diltiazem, are commonly employed ( Table 29.11). Digoxin is effective in controlling ventricular rates at rest as it prolongs AV node conduction and refractoriness through vagal stimulation, by direct effects on the AV node, and by increasing the amount of concealed conduction. However, the effect of digoxin is negated during exercise when most vagal tone is lost and AV conduction is further enhanced by the increased sympathetic tone. Digoxin alone was effective in only 58% of patients [343]. Therefore, digoxin as monotherapy can be used in older, sedentary patients, but a combination with beta-blockers or calcium antagonists is often necessary to achieve rate control in the majority of patients ( Fig. 29.35).

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Figure 29.35

24-hour Holter ECG histograms show fast ventricular rates during untreated atrial fibrillation (A), during monotherapy with digoxin (B), and after digoxin in combination with a beta-blocker (C).

Non-dihydropyridine calcium antagonists and beta-blockers are effective as primary pharmacological therapy for rate control, but multiple adjustments of drug type and dosage may be needed to achieve the desired effect [343–345]. For example, in the AFFIRM trial, only 58% of patients in the rate-control group achieved adequate rate control with the first drug or combination; drug switches occurred in 37% of the patients and drug combinations were commonly used [343]. Overall, adequate rate control was ascertained in 80% of patients at 5 years (most frequently on a beta-blocker with or without digoxin).

Physiological pacing (also see Chapter 27)

The potential to maintain AV synchrony and prevent the development of mitral regurgitation and/or ventriculoatrial conduction that could cause stretch-induced changes in atrial repolarization may lessen the chance of AF recurrence.

Atrial or dual-chamber pacing has shown some benefit over ventricular pacing alone in decreasing episodes of AF [369–372]. Meta-analysis of five major pacing mode selection trials, which included a total of 35,000 patient-years of follow-up, has shown a statistically significant 20% reduction in AF with atrial-based pacing and a 19% decrease in stroke that was of borderline significance ( Fig. 29.40) [373]. Patients with sinus node dysfunction and preserved AV conduction seem to benefit most from atrial or dual-chamber pacing. However, atrial-based pacing modes had no effect on mortality or the development of heart failure.

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Figure 29.40

Effect of pacing mode on the incidence of atrial fibrillation in a meta-analysis of five major trials: CTOPP, Canadian Trial Of Physiologic Pacing; MOST, MOde Selection Trial; PASE, PAcemaker Selection in the Elderly; UKPACE, United Kingdom Pacing and Cardiovascular Events. Modified from Healey JS, Toff WD, Lamas GA, et al. Cardiovascular outcomes with atrial-based pacing compared with ventricular pacing: meta-analysis of randomized trials, using individual patient data. Circulation 2006; 114: 11–17.

Minimizing ventricular pacing

It has been hypothesized that excessive right ventricular stimulation during dual-chamber pacing may worsen LV function and thus may negate the physiological advantage of AV synchrony and preservation of sinus node control over heart rate [374]. Thus, in patients with sinus syndrome and preserved native AV conduction enrolled in the MOST (Mode Selection Trial), the incidence of AF at 33.1 months (≈2.7 years) was 26.7% in the group assigned to ventricular-based pacing and 15.2% in the group assigned to physiological pacing [371].

The use of specific algorithms to minimize unnecessary ventricular stimulation in dual-chamber pacemakers has had no significant beneficial effect on mortality or heart failure, but has further reduced the risk of AF, in particular persistent AF, by 40% compared with conventional dual-chamber pacing [375]. In the SAVE PACe (Search AV Extension and Managed Ventricular Pacing for Promoting Atrioventricular Conduction) trial, which enrolled patients similar to those in the MOST study, the incidence of AF after 1.7 years was 12.7% in the group treated with conventional dual-chamber pacing and 7.9% in the group who treated with dual chamber-pacing plus an algorithm reducing unnecessary ventricular pacing [375].

‘Preventative’ pacing

Continuous pacing at selected sites (alternative, dual or bi-atrial) may change atrial activation patterns, increases homogeneity of left and right atrial electrical properties in conduction and refractoriness, reduce dispersion of refractoriness that occurs with premature atrial contractions (PACs) or with abrupt changes in atrial rate and thus prevent the development of atrial re-entry.

Alternative pacing sites: experimental and clinical studies have demonstrated that septal pacing, dual-site, or bi-atrial-site pacing shortens total atrial activation time [376, 377]. A number of clinical trials have evaluated the effects of selective atrial pacing sites on the prevention of AF in patients that required a pacemaker for other indications than AF, mainly with bradycardia as an indication (Bachmann bundle, inter-atrial septum) [377]. However, the largest randomized trial of right atrial pacing versus septal pacing ASPECT (Atrial Septal Pacing Efficacy Clinical Trial) failed to demonstrate a reduction in AF frequency and burden over a short follow-up [378].

Several techniques for bi-atrial stimulation have been proposed (right atrial and coronary sinus pacing) in patients with sinus node dysfunction. In the DAPPAF (Dual site Atrial Pacing to Prevent Atrial Fibrillation) trial in antiarrhythmic drug-treated patients, dual right atrial pacing increased symptomatic AF-free survival compared with support pacing or high right atrial pacing, supporting the use of a hybrid approach to rhythm management [379].

Preventative pacing algorithms: the Atrial Fibrillation Therapy (AFT) trial, which investigated modes of onset of AF to determine potential arrhythmogenic triggers, has shown that AF is most commonly caused by premature atrial complexes (PACs) (48%) and sinus bradycardia (33%), whereas sudden onset was less common (17%) ( Fig. 29.41) [380].

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Figure 29.41

Patterns of initiation of atrial fibrillation which can be modified by pacing algorithms. Atrial premature beats (APB) that trigger atrial fibrillation (A) and bradycardia preceding atrial fibrillation in vagally-mediated AF (B).

Specific algorithms are designed to prevent bradycardia and to avoid significant atrial rate variations associated with PACs. These include rate-adaptive pacing that monitors the underlying intrinsic rate to pace just above it, elevation of the pacing rate after spontaneous PACs, transient overdrive pacing after mode switch episodes, and increased post-exercise pacing to prevent an abrupt drop in heart rate.

The results of randomized clinical trials completed to date are not conclusive with respect to the beneficial effects of atrial pacing for AF and to the definition of an AF population (with except probably of patients with sinus node disease) that would obtain the most advantage from pacing strategies and which of these strategies are the best [380–384].

Atrial pacing prevention algorithms have modest to minimal incremental benefit for the prevention of AF and are not warranted in the absence of bradycardia indications for pacing [385]. At present, AF alone should not be an indication for preventative pacing, except for documented vagally-mediated AF.

‘Antitachycardia’ pacing

In some episodes, AF can be controlled with antitachycardia devices through the use of antitachycardia pacing or high-frequency atrial burst pacing. This approach is based on the concept that even AF may be sufficiently organized at its onset to allow pacing intervention, tissue capture, and arrhythmia termination [380]. Pace termination of atrial tachycardias or atrial flutter may prevent the development of AF and reduce the overall AF burden. However, when added to a pacing prevention algorithm, no further reduction of AF burden was demonstrated in a prospective randomized trial [381, 386]. In addition, there is so far no trial that demonstrates any long-term efficacy of device algorithms for both prevention or termination of AF.

Atrial defibrillator (within an implantable cardioverter defibrillator)

Initial short-term clinical experience with the ‘stand-alone’ atrial defibrillator suggested that atrial defibrillation was safe and effective. The first generation of atrial defibrillator was followed by a commercially available dual-chamber AV defibrillator. However, in a long-term analysis of 106 patients, only 39 were still actively using their device after a median of 40 months. In half, the device had been turned off or even explanted and in 14 patients it was solely used to monitor AF episodes [387]. The major drawback of internal cardioversion devices is that even a relatively low energy shock (<1J) is intolerably painful for the patient, making repetitive shocks in patients with frequent AF episodes a very unattractive treatment strategy [388].

For very selected patients who already have indications for implantable devices, device-based atrial defibrillation may be an option as a ‘backup’ option for managing AF when preventive pharmacological/electrical measures fail ( Fig. 29.42). There is limited evidence that the combination of antitachycardia pacing, atrial shock, and preventative pacing is effective in reducing AF burden [389, 390].

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Figure 29.42

Chest X-rays showing a dual-chamber cardioverter defibrillator with atrial-tiered therapies (A). Internal cardioversion of atrial flutter/fibrillation with a 1J shock via the device (B).

Hybrid therapy for atrial fibrillation

Hybrid therapy involves the use of different types of treatment which together provide some form of synergism [389]. The three available rhythm management therapies are antiarrhythmic drugs, ablation, and devices. Antiarrhythmic drugs are often used in combination with ablation or device therapy. Increasingly, ablation and device therapy is combined. Although efficacy may be improved, side effects from both therapies may occur. Hybrid therapy does not refer, however, to the concomitant use of anticoagulation or upstream therapies. This remains largely a theoretical concept that has only been strictly evaluated in a small number of studies. Principles of hybrid therapy are listed in Table 29.12.

Drug-induced atrial flutter: although atrial flutter and AF have different electrophysiological mechanisms, the two arrhythmias often coexist. Atrial flutter may initiate the first re-entrant circuit and may transform into AF as multiple wavelets develop [392]. The usual flutter pathway may continue to perpetuate AF whenever engaged. Typical atrial flutter is a relatively common finding in patients with AF treated with class IC and IA drugs and amiodarone ( Fig. 29.43). These agents may modify wavefront activation by creating lines of functional block that interrupt multiple wavelets and promote conduction preferentially through a large single re-entrant circuit such as the isthmus-dependent flutter circuit. In these patients, ablation of the cavo-tricuspid isthmus can be considered first-line therapy before proceeding to LA ablation.

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Figure 29.43

An example of hybrid therapy. A sodium-channel blocker flecainide converted atrial fibrillation into atrial flutter which was subsequently treated with isthmus ablation. Note that therapy with a sodium-channel blocker should continue after ablation to maintain sinus rhythm.

A less appreciated example of hybrid therapy is pacing for drug-induced bradycardia which allows dose up-titration to achieve the best efficacy of antiarrhythmic drugs, although the intentional use of such combination therapy is limited [393].

Other examples of hybrid therapy include pacing-induced reduction of PACs and antiarrhythmic drug modification of substrate; device-based monitoring of rate/rhythm control in AF treated by pacing or antiarrhythmic drugs; biventricular pacing and ablation of the AV node in patients with AF and heart failure.

Trigger elimination by direct focal ablation

The initial aim of AF ablation procedures was to eliminate focal triggers from within the PVs by direct localized ablation [93]. However, a trigger could only be localized when it was actually ‘firing’, a condition that was not necessary present during the procedure and was not easily provoked (pacing, pharmacological stress, etc.) [415]. In addition, multiple sites within a PV and multiple PVs could be arrhythmogenic and intra-PV ablation led to scarring of the ablated tissue and PV stenosis and/or occlusion.

Trigger elimination by pulmonary vein isolation

The initial experience led to the strategy of electrically isolating all PVs to prevent any interaction of these triggers with the atrial substrate [416, 417]. This approach was facilitated by circumferential mapping catheters that were positioned within the PV ostia to guide ablation targeting the ‘connecting’ fibres by ‘segmental’ ablation [416]. Ablation lesions were deployed relatively close to the PV ostia or just within ( Fig. 29.46), risking ostial stenosis and/or occlusion. In addition, high AF recurrence rates were reported mostly due to electrical re-conduction of the PVs, but also to some extend due to ‘ostial’ triggers in the presence of more distally isolated PVs [418–421].

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Figure 29.46

Different approaches for ablation of atrial fibrillation. The orange bolt depicts the trigger inside the left superior pulmonary vein (LSPV); red dots mark ablation sites and the shadowed yellow area demonstrates the area of isolation.

Linear pulmonary vein isolation and circumferential pulmonary vein ablation

In order to facilitate the ablation procedure and to reduce the risk of PV stenosis, the ablation sites have moved more into the atrium forming a long linear lesion around one PV or even both ipsilateral PVs together ( Fig. 29.46) [414, 422, 423], the latter having the advantage that the small space between the PV ostia (ranging from as little a several mm to cm) is spared, reducing further risk of complications [424, 425] (29.7).

There is now strong evidence suggesting that the veins and the antrum are in fact critical for maintenance of AF, rendering the classification of ‘trigger’ versus ‘substrate modification’ inadequate to fully explain the role to the PVs. In patients with paroxysmal AF, who are undergoing PVI during AF, the AF cycle length slows during ablation and AF may finally terminate in up to 75% of cases [426]. Following PV isolation of all veins, about half of patients can no longer sustain AF, suggesting that in significant proportions of patients with paroxysmal AF the PVs form the substrate maintaining AF [427].

Circumferential pulmonary vein ablation

This is a purely anatomical approach that does not require the endpoint of electrical disconnection of the encircled area ( Fig. 29.46) [428]. Since no simultaneous mapping within the PVs is performed, only a single trans-septal puncture is required. In addition, no waiting time after successful isolation is required, thereby shortening the procedure time dramatically. Using this technique up to 45% of PVs are not isolated, with persistent PV–LA conduction, which is potentially arrhythmogenic [429]. Reports from groups that have advocated the use of a purely anatomical approach have reported a significant incidence of organized arrhythmias occurring after such ablation. Indeed, a recent study reports that incomplete encircling lesions (‘gaps’) were the most predictive factor for the subsequent development of organized arrhythmias [430]. This finding argues further in favour of achieving complete lesions, with complete lesions being crucial for the prevention of macro re-entry; conversely, incomplete lesions promote the occurrence of atrial arrhythmias.

Is it really necessary to electrically disconnect the pulmonary veins? (29.10)

A recent expert consensus has recommended that complete electrical PV isolation should be achieved when treating patients with paroxysmal AF [99]. However, results from prospective trials investigating the need of permanently isolated ablation lines are still pending (e.g. GAP-AF trial).

Further evidence of the need for PVI is provided by studies that have evaluated the recurrence of AF after ablation. These studies have observed that the vast majority of patients with recurrence of AF demonstrate PV re-conduction. Repeat PVI in these patients has been associated with the elimination of AF in 90% of patients [424, 431]. In fact, patients with complete PV isolation fared best (SR in the absence of antiarrhythmic medication). Patients with re-conducting PVs with long conduction times were similar to patients with complete isolation, while patients with rapid conduction times required antiarrhythmic therapy and experienced AF recurrences [432]. These data implicate residual PV–LA connections in the development of clinical arrhythmia and serve to further accentuate the importance of achieving complete isolation. The rate of re-conduction of PVs in patients without symptomatic AF recurrences, however, is not known.

Additional lines for substrate modification

Despite exclusion of triggers, most patients with persistent or longstanding persistent AF may need additional substrate modification. The conceptual basis for substrate modification by compartmentalization of the atria is based on the multiple-wavelet hypothesis, which suggested that AF is maintained by multiple re-entrant wavelets propagating simultaneously in the atria and that a minimum mass of electrically continuous myocardium must be present to sustain the wavelets on re-entry.

Linear ablation is performed between anatomical or functional electrical obstacles in order to transect these regions and thereby preventing re-entry. A variety of different linear configurations has been investigated; however, prediction of which line is more suitable in a given patient has been elusive [433–436]. Typical applied lines are a roof line (connecting the upper PVs) or a so-called ‘mitral’ or ‘left isthmus’ line (connecting the inferior left PV to the mitral annulus (MA) ( Fig. 29.46). Ablation of the LA isthmus offers several theoretical benefits over the other LA lesions [436]. This line is short but creates a contiguous long lesion with the ablated PVs and does not interfere with normal sinus activation of the atria. In addition, its proximity to the coronary sinus allows positioning of catheters on either side of the line to evaluate the integrity of the line. However, despite these features, ablation at this site requires 20–25min of radiofrequency energy application, with 68% requiring ablation within the coronary sinus. Due to the close proximity to the circumflex artery, substantial harm may result including acute coronary stenosis requiring immediate intervention [437].

An anterior line (from the roof line to the MA) would need to cross the LA insertion of Bachmann’s bundle. This thick muscular connection between the right and LA is in fact the fastest connection between the atria and conduction block is difficult to achieve (due to the thickness of the tissue). However, complete anterior line deployment would result in a splitting of the P wave in sinus rhythm and in the presence of both a complete roof and LA isthmus line a completely isolated LAA [438].

A posterior line (between the septal and lateral PVs across the posterior wall of the LA) has been performed utilizing high power as part of the anatomical ablation strategy, leading in a number of patients to developed atrio-oesophageal fistulae [439].

Critical to the concept of linear lesions is that ablation has to be coalescent and transmural in order to achieve complete lesions. In some cases this can be challenging, with an increased procedural risk (particularly of tamponade, stroke and fistula formation). Incomplete linear lesions however may be pro-arrhythmic, resulting in rapid AV conduction of gap-related atrial tachycardia ( Fig. 29.47) [440–442]. The completeness of the line should be validated in order to avoid iatrogenic complications even though an initially ‘complete’ linear lesion may exhibit conduction gaps in the long term. In addition, thoughtful placement of lesions can help to prevent formation of macro-reentrant circuits which will result in LA flutters. Their incidence varies widely between studies (and centres), in part due to slightly different anatomical positions of ablation lines and lesions.

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Figure 29.47

Iatrogenic ‘gap-related’ atrial tachycardia post-incomplete ‘roof’ line deployment (left panel). Reentry around mitral annulus (MA) caused by incomplete ‘left atrial isthmus’ line. The white lines depict the ostia of the pulmonary veins.

After PV isolation alone, approximately 12% of patients have inducible macro re-entry and 5% present with spontaneous macro re-entry. Mapping and ablation have demonstrated that the vast majority of these use the ablated zone as a central obstacle, resulting in either peri-mitral or peri-PV re-entry being more prevalent in patients with larger atria [429].

When an anatomical approach of PV encircling has been utilized or no line validation has been performed, the reported incidence of re-entrant arrhythmias has been much higher, with some groups reporting spontaneous arrhythmias in up to 27%, presumably due to the greater but incomplete atrial ablation [441, 443, 444].

Alternative techniques for substrate modification

More recently, other techniques of substrate modification have been evaluated. The ablation of complex fractionated electrograms, without any isolation attempt of PVs has been proposed [445]. It is not clear why ablation of these points should be helpful, but reports from single centres are favourable. Interestingly, arrhythmia recurrences after such procedures seem to be dominated by arrhythmias arising from the PVs [446–450].

Several groups have described the results from ablating ganglionic plexuses (at atrial sites where a vagal response is observed after local stimulation), in addition to PV isolation [451–453]. However, long-term results of a procedure limited to these ganglia are not yet available.

Atrio-oesophageal fistula

An acutely life-threatening complication is a fistula formation between the LA and the oesophagus [439, 461]. Fortunately, this fatal complication is exceedingly rare [462] and may be avoided by careful lesion deployment along the posterior wall and energy reduction if ablation in this area is unavoidable (e.g. 30W). Static imaging of the moving oesophagus is a useless exercise that might even mislead the operator to falsely assume a ‘safe’ ablation position [463–465]. Similarly, the measurement of oesophageal temperatures can prevent some, but not all damage to the oesophagus, and might not always allow ‘safe’ ablation sites to be identified [466–468].

Pulmonary vein stenosis ( 29.11)

Using irrigated tip catheters, the current incidence of angiographic PV stenosis (>50% reduction in PV diameter) is <2%, with most patients being asymptomatic. This incidence is reduced significantly with lower-power ostial ablation and operator experience. Typical symptoms of significant PV stenosis or occlusion are persistent cough, pneumonia, and eventually haemoptysis [469–472]. The occurrence of such symptoms in a patient after AF ablation (even months later) should raise the suspicion of PV stenosis. Imaging studies such as three-dimensional MRI (or CT in patients with devices) or functional assessment of PV flow velocities using transoesophageal echocardiography should be done immediately [473, 474].

Phrenic nerve injury

This complication has been recently recognized as a consequence of catheter ablation techniques for AF. There is a close relationship between the right phrenic nerve and the superior vena cava (SVC), and the anteroinferior part of the right superior pulmonary vein (RSPV) [475]. In addition, the left phrenic nerve is close to the LAA. Phrenic nerve injury can occur independently of the type of ablation catheter (4mm, 8mm, irrigated tip, balloon) or energy source used (radiofrequency, ultrasound, cryotherapy, or laser), however it has been more often reported when using balloon-based devices [476].

Although some patients with phrenic nerve injury after AF ablation remain asymptomatic, dyspnoea is the usual presentation. While causing adverse effects on functional status and quality of life, it is reversible in the most patients. However, recovery of PNI may take up to 1 year. High output pacing can be used to identify the PN and allows an exact three-dimensional localization to avoid ablation in immediately adjacent area [476].

Tamponade

Cardiac tamponade occurs either during the trans-septal puncture, mechanically during the mapping process, or during the ablation itself by steam-pop formation [477]. The incidence varies in reports from as low as 0.6% to up to 2.9% and is clearly associated with the experience of the operators [478, 479]. Most tamponade can be handled successfully by immediate pericardiocentesis; a small minority of patients however, require surgical drainage.

Thromboembolic events during and after ablation

Clot formation at the LA catheters is thought to be the cause of thromboembolic events during AF ablation ( Fig. 29.49). While transoesophageal echocardiography is recommended prior to LA access to rule out any pre-existing LAA thrombus, small existing thrombi may be overlooked and dislocated mechanically during the mapping procedure [99]. The Worldwide Survey I quotes a 0.93% incidence for all events, ranging from TIAs with 0.66% to stroke with 0.28% [329]. To avoid intraprocedural events, close observation of activated clotting time (ACT) at regular intervals (e.g. every 30min) is recommended to allow individual adjustment of the anticoagulation parameters by intravenous heparin. As stated by expert consensus, oral anticoagulation should be continued for a minimum of 2 months after catheter ablation and thereafter according to the individual CHADS₂ score [98].

Death

Death is a relatively rare complication, occurring in approximately one of 1000 patients undergoing ablation for AF. In the Worldwide Survey II which reported on >45,000 procedures in >32,000 patients, causes of death included tamponade in eight patients, stroke in five, atrio-oesophageal fistula in five, and massive pneumonia in two patients [480]. Other causes of death included myocardial infarction, sudden respiratory arrest and asphyxia, torsade de pontes, pulmonary vein occlusion and perforation (extrapericardial), septicaemia, and intracranial bleeding.

Anticoagulation

Initially post-ablation, LMWH or intravenous heparin should be used as a bridge to resumption of systemic anticoagulation for a minimum of 2 months. Thereafter, the individual CHADS₂ score of the patient should determine if oral anticoagulation should be continued. Discontinuation of warfarin therapy postablation is generally not recommended in patients who have a CHADS₂ score of 2 or more [99].

Monitoring for atrial fibrillation recurrences

The most appropriate assessment of the clinical mid- and long-term outcome after AF ablation still remains a subject of discussion. Currently evaluation is usually based on Holter ECG, tele-ECG, or on patients’ symptoms. A high prevalence of asymptomatic episodes of AF has been revealed indicating that patient interrogation alone may not be suitable for an accurate follow-up due to an overestimation of freedom from AF. Although antiarrhythmic medication is continued for some time (up to several months) in most studies, results should be reported off drugs with all atrial arrhythmias (including atrial tachycardia or frequent atrial premature beats) counting as failure [8, 99].

While 7-day Holter ECG has demonstrated that many AF episodes may not be recognized by the patient post-AF-ablation [503], a recent study in patients with pacemakers demonstrated a clear correlation between symptoms and AF recurrence [504]. The expert consensus recommends following AF ablation patients in 6-month intervals for at least 2 years, after an initial follow-up visit at 3 months [99]. However, as the indication for ablation is relief of symptomatic AF episodes, the therapeutic outcome can be monitored by symptom-driven ECGs in many routine clinical settings.