Current Considerations in Atrial Fibrillation

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Atrial fibrillation (AF) is the most common sustained clinical arrhythmia. The disease has a significant socioeconomic impact, with the annual cost of treating AF estimated to be about US$3,600 per patient. Although not directly life-threatening, AF also creates a growing and significant medical impact and is associated with an increased long-term risk of stroke, heart failure, and allcause mortality, especially in women. Several studies have shown that the mortality rate of patients with AF is double that of patients with normal sinus rhythm and is linked to the severity of underlying heart disease.1
The estimated size of the burden of AF in the US varies depending on the source, but in general it is thought that approximately 2–2.5 million people in the US have AF.2 The percentage of people with AF increases with age. As one gets to the 80+ age group, 10% of the population will be affected by AF.2,3 Furthermore, the incidence of AF appears to be increasing: a key reference study estimates that by 2050, 5.6 million people in the US will be affected by AF.2 A more recent study, conducted in Minnesota by the Mayo Clinic, estimates that the number of people affected with AF will approach 15.9 million by 2050.4 The differences between the two studies can be explained by a variance in the studied populations; the earlier study looked at patients of a health maintenance organization, which is a specific population, while the more recent Minnesota study focused on an entire population in the Midwest. In addition, the Minnesota study cites previous underestimates of the increased prevalence of atrial fibrillation due to aging and points to an increase in the incidence of AF among people suffering from obesity.4 The current figures may also represent a substantial underestimation of the problem. At least one-third of episodes of AF go undetected;5,6 taking this into account, the 2–2.5 million mentioned above may in fact be 30% higher.
Although much has been learned about AF in recent years, several questions still remain, especially in terms of its pathogenesis and prognosis. A limited understanding of the disease has also hampered the management of AF. In 2006, the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) published updated guidelines for the management of AF.1 The updated ACC/AHA/ESC guidelines are the first revisions to AF management recommendations since 2001. Previous proposed classification schema did not fully account for all aspects of AF and several different labels and nomenclature have been used to describe patterns of AF, including acute, chronic, paroxysmal, intermittent, and permanent.

However, these definitions can be confusing and make the comparison of results of studies that assess the magnitude and treatment of AF difficult. The ACC/AHA/ESC guidelines suggest that AF be classified into three patterns, as follows: paroxysmal AF—self-terminating within seven days; persistent AF—requiring cardioversion or lasting seven days or more; and permanent AF—persisting a year or more, or where cardioversion has failed or has been foregone. Recurrent AF is considered to be present when a patient has two or more episodes of AF and first-detected AF may be either paroxysmal or persistent. This terminology does not apply to secondary AF in the setting of acute myocardial infarction (MI), cardiac surgery, pericarditis, myocarditis, hyperthyroidism, or acute pulmonary disease.

Impact of the Guidelines

It is extremely difficult to estimate the impact of guidelines on clinical practice. Unfortunately, there is a gap between writing and publishing guidelines and the application of those guidelines and often, the actual application of consensus guidelines leaves much to be desired. A new approach that could help facilitate the application of clinical guidelines would be the creation of a website into which a physician can input his or her patient’s parameters. Accordingly, the website can then supply specific guidelines applicable to that patient together with the level of evidence. For example, the Framingham website allows a physician to input patient parameters in order to determine a risk score for developing coronary artery disease.7 This same concept could be applied to guidelines. If we can facilitate the ease of use of the guidelines with such a mechanism, it may be that we will have increased use and application of the guidelines.
The ACC has established an initiative called Guidelines Applied to Practice (GAP), which aims to improve the quality of cardiovascular care by bringing ACC/AHA practice guidelines to the point of care. The program consists of a series of projects to develop and test tools and strategies for implementing guidelines.8 The AHA and American Stroke Association have also established a similar concept called Get With the Guidelines (GWTG). GWTG is a hospital-based quality improvement program and aims to get physicians to treat heart and stroke patients consistently according to the most up-to-date guidelines.9 Both GAP and GWTG have shown that if one intensively educates physicians and hospital support staff about guidelines, one can dramatically impact overall survival, cessation of smoking, treatment of AF, treatment of cholesterol, etc.

The treatment of AF has two mandatory aspects: adequate control of the ventricular rate and adequate anticoagulation therapy. An eventual goal will be restoration and maintenance of sinus rhythm. Inadequate treatment can lead to heart failure with uncontrolled ventricular rate. Inadequate anticoagulation is associated with an increased risk of stroke. These are the two major areas that need to be stressed and are underscored in the consensus guidelines. While two landmark randomized controlled trials—the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) and the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) trials—have shown that a strategy aimed at restoring (and maintaining) sinus rhythm neither improves the survival rate nor reduces the risk of stroke compared with a strategy of rate control and anticoagulation.10,11 There is still a need for additional prospective, randomized controlled trial data to indicate whether patients with symptomatic or asymptomatic AF do better in the long term simply with rate control and anticoagulation or with aggressive attempts to maintain sinus rhythm with repeated electrical cardioversion and antiarrhythmic agents.
This is because there were important limitations to these studies. Both studies primarily enrolled older patients (over 65 years of age) with persistent AF who were mildly symptomatic. Furthermore, in the AFFIRM study, fewer than two-thirds of those in the rhythm control arm were actually able to maintain normal sinus rhythm. Because of these limitations it is difficult to extrapolate the results to certain subgroups of patients. These include: younger patients; those with new, first-onset AF who may benefit from early conversion to sinus rhythm; patients with persistent AF who are highly symptomatic; and patients with poor left ventricular function or with significant heart failure.
The latest ACC/AHA/ESC guidelines also made two important changes to clinical recommendations. The guidelines now include the use of catheter ablation of AF as one of the therapeutic options for patients with more persistent AF. Furthermore, in the anticoagulation guidelines, the threshold for anticoagulation has actually been lowered and the guidelines now are quite specific about risk factors for stroke in various risk groups.1

The Progression of Atrial Fibrillation

AF is a tachycardia-induced atrial cardiomyopathy. Atria beating at 3–400 to 600 beats per minute create an atrial cardiomyopathy that will subsequently transform the atria both structurally and functionally into a substrate that facilitates the maintenance of the AF. The experimental work of Wijffels and colleagues produced the theory known as ‘AF begets AF.’12 The researchers, using rapid atrial pacing to provoke AF in goats, revealed that electrical, cellular, and metabolic changes in the atrium occur within 24 hours after AF is produced. Moreover, they observed electrical changes—such as shortening of the refractory period and action potential duration—within six hours of provoking AF. Nattel et al. have shown that these changes were associated with alterations in the function of cellular membrane channels that control the electrical and contractile function of cells. Application of this theory led to management strategies such as early cardioversion and atrial pacing to prevent AF, and treatment with atrial defibrillators that seek to avoid progression of paroxysmal and persistent AF to permanent AF by reducing the frequency and duration of episodes of AF.
A number of studies, including the Framingham Heart Study13,14 and the Cardiovascular Health Study5 have shown that factors such as the development of heart failure, coronary disease, and hypertension can also contribute to altering the atrial substrate and facilitate the development of AF. A recent study produced data complimentary to the Framingham Heart Study and the Cardiovascular Health Study (CARAF). The CARAF study investigated the natural history of paroxysmal AF after initial discovery. The study enrolled 757 patients at the time of first diagnosed paroxysmal AF, of whom 63% had electrocardiographically documented recurrence within five years. The investigators found that paroxysmal AF progressed to chronic AF in 8.6% of the study population by year one and in 25% by year five. The study defined risk factors similar to those reported by the Framingham and the CARAF studies. These include increased left atrial size, age, cardiomyopathy, aortic stenosis, and mitral regurgitation.

Interestingly, the CARAF study showed that even a relatively mild degree of left atrial enlargement was associated with increased risk of developing permanent AF. Furthermore, higher ventricular response rates during AF were linked to a lower probability of progression to permanent AF.15 It is also important to emphasize that, from these data, progression to chronic AF is not inevitable.

Conclusion

AF has gained increasing importance and is currently the most common sustained cardiac arrhythmia in the US and Europe. The impact of AF is expected to grow significantly due to an increasing prevalence associated with an aging population and the growing problem of obesity. The heterogeneous nature of the AF population and a limited understanding of the disease has complicated management options. However, as our understanding of the pathogenesis and natural history of AF grows, this will hopefully lead to new approaches towards treatment and prevention. The non-invasive solutions have, in general, have been relatively insufficient and the non-pharmacological approaches have been better. The latest ACC/AHA/ESC guidelines have two important changes in clinical recommendations. The guidelines now include the use of catheter ablation of AF as one of the therapeutic options for patients with more persistent AF. Furthermore, in the anticoagulation guidelines, the threshold for anticoagulation has actually been lowered and the guidelines now are quite specific about risk factors for stroke in various risk groups. Pharmacological development needs to move its focus from finding the ‘son’ or ‘grandson’ of quinidine and search for new approaches. 

References
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