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An overview of treatments for atrial fibrillation
Inderjeet Singh Sahota1
1. Department of Biomedical Physiology and Kinesiology, Faculty of Science, Simon Fraser
University
Department of Biomedical Physiology and Kinesiology
Faculty of Science
Simon Fraser University
8888 University Drive
Burnaby, B.C.
Canada
[email protected]
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ABSTRACT
Atrial fibrillation (AF) accounts for almost one-third of all hospital visits regarding cardiac rhythm
disturbances. X-rays, blood tests, echocardiograms and electrocardiograms, in addition to medical
histories and physical examinations, aid clinicians in diagnosing patients with AF. Classifying AF is
complex and no current classification system accounts for all aspects of the pathology although the
present widespread system classifies AF temporally and by pattern of recurrence. However, treatments for
AF focus on the patient’s symptoms, not on their pathological classification. In acute, emergency
situations the treatment priority is in maintaining haemodynamic stability whereas long-term management
of AF is more complex as numerous factors, such as age, other medication, symptoms and current or
previous diagnosis of heart disease, influence treatment. Anticoagulation, rate control, rhythm control and
various non-pharmacological treatment options for long-term treatment of AF are discussed in more
detail. Clinicians should discuss issues regarding quality of life and adverse side effects of each treatment
with their patients. As a cure for AF currently does not exist, treatment protocols should be focused on
improving quality of life and minimizing adverse risks associated with the pathology.
KEYWORDS: Atrial Fibrillation, Pharmacology, Treatment, Cardiology
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MANUSCRIPT TEXT
Introduction
Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia accounting for approximately onethird of all hospital visits regarding cardiac rhythm disturbances.1 AF is characterized by non-coordinated
atrial contraction, which results in quivering or fibrillation of the atria. This fibrillation decreases the
efficiency of circulation which may lead to syncope, chest pain, congestive heart failure or stroke. Most
studies examining the incidence of AF have been performed in the United States or in Europe. The
Framingham Study in the USA2 and the Rotterdam Study in Europe3 determined that the lifetime risk of
developing AF is approximately 25% for both men and women over 40 years of age. In the general
population the prevalence of AF is somewhere between 0.4% and 1% and can increase to 8% for those
over 80 years of age.1 Furthermore, AF is an expensive condition to treat, costing approximately $3,600
USD annually per patient.4
Diagnosing Atrial Fibrillation
Upon presentation, the clinician has a number of tools available to help diagnose the presence of
AF. A medical history and physical examination are routinely used tools that allow the clinician to
determine prior or familial history of cardiovascular disease and check for signs of structural heart
disease. Other tools such as chest x-rays, blood tests and echocardiograms allow for further elucidation of
the pathology. Echocardiograms are increasingly used tools that allow clinicians to determine whether
there have been any changes to the structure of the atria as well as help determine atrioventricular valve
morphology and function. Transesophageal echocardiography (TEE), a subcategory of echocardiography,
specifically allows for detection of thrombi within the atria and is commonly used to help determine
anticoagulation treatment strategies. Furthermore, electrocardiography (ECG) is crucial in diagnosing a
person with AF. Commonly, a 12-lead ECG is performed and markers such as missing P-waves,
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substituted by fibrillatory waves, and variable QRS complex frequencies are used as signs indicating the
presence of AF.5
Issues in Classifying Atrial Fibrillation
The classification of AF is by no means a trivial process. Due to the complexity of its presentation
no current classification system accounts for all aspects of AF.1 Some systems have been based on ECG
presentation alone6 whereas many other clinical classifications have been created in an attempt to simplify
the classification process.7, 8 Currently, the most widely accepted classification system for AF is one in
which AF is divided temporally and by pattern of recurrence.1 In this system, AF is categorized into any
one of the following:
Recurrent:
If AF occurs more than once
Paroxysmal: If recurrent AF terminates spontaneously within 7 days
Persistent:
If recurrent AF is sustained beyond 7 days
Permanent:
If AF is on-going (> 1 yr) and cardioversion is unsuccessful or untried
Treatment Options for Atrial Fibrillation
Regardless of the classification, the treatment of AF is based upon the symptoms that the patient
exhibits9. The management of AF typically involves 5 steps: (1) controlling the ventricular rate, (2)
restoring sinus rhythm via cardioversion, (3) preventing the recurrence of AF, (4) long-term rate control
and (5) preventing thromboembolism.10 In an emergency situation the priority is to maintain
haemodynamic stability by cardioversion. After attaining stability ventricular rate control drugs and fastacting anticoagulants should be administered. Finally, should the patient remain in AF for over 48 h the
clinician could consider TEE-guided cardioversion or 3 weeks of anticoagulants followed by
cardioversion. If the AF episode is under 48 h the risk of stroke is minimal and pharmacological or
electrical cardioversion are indicated.11 The management strategies for chronic AF situations will be
covered in further detail later but are more complicated as confounding factors such as previous heart
disease, other lifelong medications and age need to be taken into consideration.
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Due to the complexity of AF, no cure for the condition presently exists. Current treatments for AF
focus on reducing the likelihood of recurrence as well as preventing secondary complications. The
treatments for AF can be divided into anticoagulation, pharmacological rhythm control, rate control and
other non-pharmacological techniques. The mechanism of these treatments, their clinical use and
management protocols will be discussed next.
Anticoagulation
Unlike the other treatment categories for AF, anticoagulation does not attempt to treat the primary
phenotypes of AF. Anticoagulation treatment instead attempts to address a serious secondary
complication of AF, thromboembolism, with a specific focus on reducing the incidence of stroke. There is
a 4 to 5-fold increase in the risk of stroke for people with AF regardless of the type of AF they have 9 with
an increase in risk with ageing. By the time an AF patient is 80 years of age or older the risk of stroke per
year becomes a staggering 24% or higher.12 Risk of stroke is an important consideration clinicians need to
make when caring for an individual with AF and anticoagulation therapy is crucial in minimizing this
risk.
The mechanism underlying increased thrombi formation in AF involves changes in
haemodynamics within the atria. In AF there is little effective contraction of the atria which results in
stasis of the blood. In susceptible individuals this stasis can lead to the formation of thrombi within the
atrial chamber which could dislodge and embolize to the brain causing stroke. Thromboembolism is not
limited to the brain and could potentially occur anywhere in the vasculature; however, these cases are
usually less serious. The complete mechanism behind increased thrombus formation in AF is more
complex and involves various factors included in Virchow’s triad. Watson et al provide a more detailed
explanation.13 However, the above description will suffice for our summary purposes.
Many different types of anticoagulants are available for individuals with AF; all with their
inherent pros and cons. Aspirin, warfarin, heparin, antiplatelet combinations and other nonpharmacological options are current anticoagulation treatments often described in the literature. Aspirin, a
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common analgesic medication, also has an antiplatelet effect by inhibiting the production of thromboxane,
a protein that binds platelet molecules together.14 Together with clopidogrel, another antiplatelet
medication, aspirin forms the basis of many antiplatelet combinations used as anticoagulant treatments.
Warfarin, another more commonly used anticoagulant treatment, has a different pharmacology. Warfarin
belongs to a class of drugs called Vitamin K Antagonists that exert their effect by inhibiting the action of
vitamin K which normally increases production of various clotting factors in the body.15 Heparin’s
pharmacology is less well described but its anticoagulant properties are thought to originate with
heparin’s ability to inhibit the enzyme anti-thrombin which inactivates the protein thrombin.
Various studies over the last 5-10 years have looked at the efficacy of these different treatments in
reducing stroke risk.16, 17 Aspirin has been shown to reduce the risk of stroke by approximately 22%,18
considerably lower than the 64% reduction seen with warfarin.19 Warfarin, therefore, remains the most
efficacious anticoagulant currently available and most guidelines unanimously declare that warfarin, not
aspirin, should be prescribed for AF patients who are at an intermediate to high risk of developing stroke.1
However, this increased efficacy of anticoagulation with warfarin comes at a price. The risk of
haemorrhage with warfarin is over double of that for aspirin20; therefore, aspirin is still recommended as
an anticoagulant for AF patients who are at a low risk of stroke. Another drawback to warfarin is that
people on this lifelong medication require routine monitoring to determine whether their INR levels
(International Normalized Ratio, a measure of the clotting tendency of blood) maintains within a range of
2.0-3.0.1 Should the INR value increase beyond that the patient is at an elevated risk of haemorrhaging.
Heparin as an anticoagulant is administered almost exclusively in emergency situations. Unlike warfarin,
which takes several days to exert a therapeutic effect (and another several days for clearance), heparin has
an immediate anticoagulant effect and can be discontinued rapidly. Heparin’s anticoagulation efficacy is
also similar to warfarin’s. However, as heparin can only be administered intravenously or by injection, it
is less useful as a long-term treatment in comparison to warfarin and aspirin which can be administered
orally. Antiplatelet combinations are generally not recommended for anticoagulation therapy above
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warfarin as the combination of aspirin and clopidogrel has shown to reduce the risk of stroke by only
22%.19 However, after percutaneous coronary intervention the ACC/AHA/ESC 2006 guidelines
recommend that antiplatelet combination therapy be used for at least 1-12 months before warfarin is used
alone.1 The elevated risk of bleeding post-surgery means warfarin is contraindicated in these situations.
Two non-pharmacological options for decreasing the risk of stroke in patients with AF are prominent in
the literature: closure of the left atrial appendage (LAA) and insertion of a transcatheter occlusion device
(i.e. Watchman®). Both of these treatments act to block the LAA from the rest of the left atrium as
previous studies have shown that over 90% of all thrombi are formed in the LAA, possibly due to specific
local haemodynamics.10,
21
In summary, treatment with warfarin is advised for most AF patients who
require anticoagulation. However, specific risks associated with warfarin such as haemorrhaging must be
considered and determination of whether an AF patient is at a high enough risk of stroke to warrant taking
warfarin must be evaluated.
An important aspect of anticoagulation treatment for patients with AF is determining and
categorizing what risk they are at for developing stroke. Knowing a patient’s risk helps advise treatment
and various risk stratification systems have been created in the past for this purpose. The most recent risk
stratification guidelines, the NICE guidelines and the ACC/AHA/ESC guidelines, both categorize risk of
stroke in a similar manner. Both guidelines group AF patients into low, intermediate and high risk
categories and have a large emphasis on age, prior history of stroke, TIA or other thromboembolic events,
and other confounding factors such as hypertension, diabetes and vascular disease.11 According to the
NICE guidelines AF patients under 65 yrs with no history of embolism or other confounding factors for
stroke are grouped as low risk. Patients over 65 yrs with no high risk factors or patients under 75 yrs with
hypertension, diabetes or vascular disease are considered intermediate risk. Finally, high risk patients are
those that have had previous ischemic stroke, TIA or thromboembolic event, are over 75 yrs old with
other risk factors for stroke and have evidence of heart disease or impaired left ventricular function.22
Treatment protocols are based on risk category where low risk patients are recommended anticoagulation
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with aspirin (75-300 mg/day) and intermediate and high risk patients are recommended anticoagulation
with warfarin (INR: 2.0-3.0). A final treatment protocol for anticoagulation that requires mention is
anticoagulation treatment before either pharmacological or electrical cardioversion. Pharmacological
cardioversion is a major treatment for AF; however, before cardioversion can be started the risk of
developing a thromboembolic event with cardioversion must be taken into consideration. If a patient’s
duration of AF is under 48 hours most guidelines deem them safe to undergo immediate cardioversion
treatment. If a patient’s duration of AF is greater than 48 hours, however, guidelines recommend that
clinicians either determine whether any thrombi exist in the atria (via TEE) or anticoagulate the patient for
3 weeks prior to cardioversion.11 The risk of thromboembolism is greatly increased upon initiation of
cardioversion as any thrombi that may have formed and remained in the atria may be dislodged into the
vasculature when the dynamics of heart contraction are altered with cardioversion.
In summary, many anticoagulation treatments exist for patients with AF. Drugs such as warfarin
currently reduce the risk of stroke the greatest; however, this comes at a price of increased risk of
haemorrhaging and the need for routine monitoring. Risk stratification systems are designed to account
for different aspects of stroke risk and categorize AF patients into those at most risk of developing stroke
and those at least. Once patients are categorized to a risk group they are treated accordingly. However, the
process is often complex and clinicians may opt to change anticoagulation treatments depending on a
patients response to the drug regardless of their risk stratification. Upon starting rate control or rhythm
control treatment most patients will also be prescribed lifelong anticoagulation treatments and, therefore,
the search for new anticoagulants with reduced complications and higher efficacies are warranted.
Rate & Rhythm Control
Drugs for rate control and rhythm control of the heart are the 2 main pharmacological treatments
for AF. Rate control therapies focus on, as the name implies, controlling the overall heart rate. In this type
of treatment the atria are left fibrillating and drugs attempt to control the ventricular rate by altering
conduction through the atrioventricular (AV) node.23,
24
Rhythm control therapies, on the other hand,
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24
attempt to restore normal sinus rhythm and address the fibrillation itself. Before describing how each of
these therapies work separately in more detail it’s important to understand how each type of therapy
compares and whether one therapy is preferred over the other in certain situations.
Traditionally it had been common practise to prescribe rhythm control drugs in favour of rate
control drugs as AF is related to increased risk of cardiovascular disease and rate control drugs do not
address the fibrillation itself. For this reason rhythm control drugs were considered better options.
However, recent studies have indicated that the rate of death or other morbidities is not higher in patients
undergoing rate control treatments and as rhythm control treatments are associated with many other risks,
rate control treatments are a viable option.25 Some of the advantages of rate control treatment include the
avoidance of potentially dangerous antiarrhythmic agents and better cost effectiveness while maintaining
similar risks of stroke and mortality as rhythm control therapies. A significant drawback to rate control
treatment, however, is that as the AF is left unchecked there can be significant permanent atrial
remodelling. This can have knock-on effects and may preclude somebody to developing other cardiac
diseases. Rhythm control treatments, alternatively, offer better haemodynamic function and may not
affect quality of life as much, especially for more active people, as rate control drugs limit the maximal
heart rate. Some disadvantages of rhythm control drugs, one of which has previously been mentioned, is
that they can have serious side effects, are expensive and are associated with increased hospitalizations.26
Whichever treatment option is chosen the clinician needs to take these advantages and disadvantages into
account and determine which type of therapy will work best for each patient. As a rough guideline, rate
control therapy may be preferred in less symptomatic elderly patients (as achievement of higher maximal
heart rates may not be as important) whereas rhythm control therapy may be preferred in younger patients
or patients with lone AF as rhythm control drugs do not require as much anticoagulation treatment.22
There are 3 types of rate control treatments currently used in clinical practise: cardiac glycosides,
β-blockers and Ca2+ channel blockers. The mechanism of action for cardiac glycosides, such as digoxin, is
still not completely understood. They are believed, however, to decrease the function of the Na+/K+
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ATPase and to increase the activity of the vagus nerve. These activities cause digoxin to, 1) increase the
contractility of the heart and, 2) decrease transmission of the electrical impulse through the AV node
thereby decreasing the heart rate. β-blockers have a very different mechanism of action. β-blockers, or βadrenergic antagonists, are drugs that primarily block the β1 and/or β2 receptors in the heart and
vasculature which normally bind epinephrine and norepinephrine; two molecules associated with the
sympathetic nervous system response. By blocking these receptors, β-blockers prevent the heart from
increasing its contractility and rate upon sympathetic nervous system activation.27 Three examples of
commonly used β-blockers used in AF rate control treatment are esmolol (β1-specific), metoprolol (β1specific) and propranolol (non-selective acting on both β1 and β2 ). Finally, Ca2+ channel blockers work,
as the name implies, by blocking L-type Ca2+ channels preventing Ca2+ from entering the myocyte and
thus decreasing contractile force and rate. Some examples of commonly used Ca2+ channel blockers are
diltiazem and verapamil. Rate control treatments (with the exception of digoxin) are commonly used as
acute treatments for AF as they can be administered intravenously and can exert their effects rapidly.26
However, different rate control drugs are used depending on other confounding factors the patient may
have. For example, diltiazem is less negatively inotropic than verapamil and may be preferred as it exerts
less effect on the peripheral vasculature. For patients who are exhibiting high adrenergic tone upon
presentation, any of the intravenous β-blockers would be beneficial as they would reduce the ventricular
rate and have a sympatholytic effect on the high adrenergic tone. Finally, if patients are also presenting
signs of heart failure digoxin may be the rate control drug of choice due to its positive inotropic and
negative chronotropic effects.10 The acute treatment of AF using rate control therapy can also be divided
by the haemodynamic stability of a patient upon presentation with diltiazem, verapamil, esmolol,
metoprolol and propranolol indicated for patients who are haemodynamically stable, digoxin and
amiodarone (an AV node inhibitor) indicated for patients who are haemodynamically stable but
hypotensive and direct current cardioversion for those who are haemodynamically unstable.28 Chronic
rate control treatment of AF patients usually involves multiple drug types with the overall goal of
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1
controlling the resting heart rate between 60 and 80 beats per minute. Usual treatment involves either 1
or 2 rate control drug types, although it is not uncommon to require 3 rate-controlling agents.
Class I (Na+ channel blockers) and class III (K+ channel blockers) are two common rhythm control
drugs used for the treatment of AF. Class I anti-arrhythmic drugs (AADs) can be further divided into
intermediate association/dissociation Na+ channel blockers (Ia), fast association/dissociation blockers (Ib)
and slow association/dissociation blockers (Ic). According to the Vaughan Williams classification
system,29 class III drugs do not subdivide further. Class Ia drugs, such as quinidine and disopyramide,
were commonly used in the past to treat AF. Due to safety reasons, however, they have now been
replaced by class Ic drugs such as flecainide and propafenone. Class Ic agents seem to have very high
efficacy in comparison to other AADs1 but also raise questions of safety themselves as flecainide can be
proarrhythmogenic and is now contraindicated in people with structural heart disease. According to the
newest 2006 ACC/AHA/ESC guidelines flecainide and propafenone are only recommended when there is
no structural heart damage and more focus is now placed on class III treatments which may not be as
efficient but are generally not as high risk.1 Class III AADs for rhythm control treatment of AF include
sotalol, ibutilide and dofetilide. Amiodarone is another drug normally labelled as a class III AAD
although it has multiple actions and can sometimes behave like class Ia, II and IV AADs as well. The
ACC/AHA/ESC guidelines recommend the following for the maintenance of sinus rhythm with rhythm
control drugs. For AF patients with no structural heart disease flecainide, propafenone and sotalol should
be the first line treatments followed by amiodarone or dofetilide should the former be ineffective. For
hypertensive AF patients without substantial left ventricular hypertrophy the same treatment as described
for patients with no structural heart disease should be used. If a hypertensive AF patient does have
significant hypertrophy, however, class Ic drugs are not recommended and instead amiodarone should be
the first line treatment. For AF patients with coronary artery disease dofetilide and sotalol are indicated
followed by amiodarone should the previous 2 be ineffective. Finally, for AF patients with a heart failure
condition amiodarone and dofetilide are the only pharmacological options for maintaining sinus rhythm1.
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Patients undergoing pharmacological rhythm control therapy may also be able to start a “pill-in-thepocket” type of treatment whereby he or she could carry pills such as flecainide or propafenone with them
at all times and take one whenever they feel the onset of AF. If clinicians feel this option is possible the
patients will first have to take these medications in a hospital setting to account for any potentially fatal
arrhythmias that could be associated with the drugs.
In summary, rhythm control treatments are more efficacious than rate control treatments and
address the fibrillation itself. However, rhythm control treatments have much higher arrhythmic risks
associated with them30 and, although they are meant to prevent arrhythmia , in many times, can be proarrhythmogenic themselves. Studies have shown that rate control treatments can be a viable alternative to
rhythm control therapy although problems such as atrial remodelling would need to be addressed.31, 32 For
a clinician attempting to treat a patient with AF it is important that he or she take each patient case-bycase accounting for any other confounding factors. The clinician and patient should also discuss the
quality of life issues associated with each treatment together before coming to any conclusions on longterm treatment.
Non-pharmacological Treatments
The limited efficacy and high risk of arrhythmia associated with AADs has led to the further
exploration of non-pharmacological treatments. Unlike pharmacological treatments that may or may not
act on the atria, all non-pharmacological treatments work on the atria and, therefore, act to reduce the
incidence of AF itself.11 There are many types of non-pharmacological treatments for AF; however, this
paper we will focus on 3 broad categories: surgical procedures, ablation and atrial pacing.
Various surgical procedures can be performed to help treat AF. One surgical procedure, called the
corridor procedure, was first described in 1985.33 In this procedure the atria are divided into 3
compartments: right atrium, corridor from SA to AV node and left atrium. Only a small corridor region of
the atria is left intact which allows the impulse to reach the AV node and allow for ventricular
contraction. Rate control is achieved as the SA node is still able to transmit impulses to the ventricles,
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however, this procedure leaves the atria fibrillating and has now been replaced by more advanced
surgeries.34 One of these more advanced surgeries currently being used is the Cox Maze procedure. This
procedure requires a major heart surgery which carries with it its own risk of mortality and morbidity,
however, studies have shown for it to be effective at treating the AF. The Cox Maze procedure essentially
works by cutting the atrial walls into specific patterns forcing depolarization wave fronts to travel in a
particular direction. By forcing these patterns it’s hoped that re-entry will not be possible and recurrent
AF incidence will consequently be reduced.35 There have been reported success rates of 85% to 95% for
this technique.36 Also, if the LAA is removed or appropriately closed during the surgery the long-term
stroke rate has been shown to be very low.37 The Cox Maze procedure, therefore, seems to be a good
option for patients who are suffering with AF. As it involves a major operation, however, this procedure,
as well as other surgical procedures, is best reserved for those patients whose quality of life is being
affected by the AF.38
Surgical procedures, although effective, can be dangerous; therefore, finding a procedure that is
less invasive is preferred.38 One such procedure is ablation, the most common of which is radiofrequency
ablation. Radiofrequency ablation works by emitting high-frequency alternating current through catheters
inserted into the atria. These catheters are placed at the specific areas where electrical activity of the atria
is more disrupted. Electrodes on the ends of these catheters allows for the detection of electrical activity
within different sections to help determine which areas may be the sites of arrhythmogenesis. By creating
lesions over these areas, radiofrequency ablation attempts to prevent AF by destroying the sites in the
atria where these arrhythmias form.34 Although ablation techniques are effective, it has been suggested
that their use be restricted to patients with severe symptoms in whom other treatments were unsuccessful.
Ablation, after all, permanently destroys parts of the heart and if other less mutilating procedures become
available in the future it may be too late for those that have undergone ablation procedures.39 Another
drawback to radiofrequency ablation is that many are performed at the AV node in an attempt to slow
down ventricular rate via destruction of some of the conduction pathways. This technique has been shown
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38
to be effective; however, it renders the patient pacemaker-dependent,
which moves us to the next non-
pharmacological treatment option.
The final non-pharmacological treatment for AF that will be discussed is the atrial pacemaker.
Atrial pacing, opposed to ventricular pacing, prevents pauses and escape beats in the atria that may cause
fibrillation.40 Ventricular pacing alone leaves the atria pacing with the SA node which does not protect it
from events that may cause fibrillation. Pacemakers may be especially useful for patients whose AF is of
a vagal origin. In normal conditions, stimulation of the vagus nerve causes bradycardia. If a patient’s AF
is triggered by a reduced heart rate a pacemaker may help prevent this reduction from occurring.40
However, the use of pacemakers is limited. Pacemakers may reduce the chance of AF occurring but
cannot stop an AF episode that has already started. Therefore, it’s efficacy as a treatment is limited and
may be suitable as only a secondary measure, for those patients who have undergone ablation, or as a
primary measure for only a very select subgroup of AF patients.34
Summary
Atrial fibrillation is a complex disorder that has many different treatment options but no single
cure. Treatment of AF focuses on the primary condition, the fibrillation itself or secondary complications,
such as thromboembolism. Therapies such as pharmacological rate and rhythm control as well as nonpharmacological/surgical procedures focus on the primary condition but have their own inherent risks. In
almost all pharmacological treatments anticoagulation is vital in decreasing the risk of stroke. Clinicians
should be advised to carefully discuss with an AF patient differences in quality of life issues with each
treatment and whether any treatments are contraindicated for that person depending on their history of
previous heart or cardiovascular disease. Each treatment carries with it its own risks and prescription of a
particular treatment can vary largely individual to individual. As a cure for AF currently does not exist,
treatment protocols should be focused on improving quality of life and minimizing adverse risks.
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CONFLICTS OF INTEREST
None to report.
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