Atrial Fibrillation Treatment & Management

The cornerstones of atrial fibrillation management are rate control and anticoagulation^[24] and rhythm control for those symptomatically limited by AF. The clinical decision to use a rhythm-control or rate-control strategy requires an integrated consideration of several factors, including degree of symptoms, likelihood of successful cardioversion, presence of comorbidities, and candidacy for AF ablation (eg, pulmonary vein electric isolation or MAZE procedure).

Restoration of sinus rhythm with regularization of the heart's rhythm improves cardiac hemodynamics and exercise tolerance. By maintaining the atrial contribution to cardiac output, symptoms of heart failure and overall quality of life can improve. As AF contributes to pathologic atrial and ventricular remodeling, restoration of sinus rhythm can slow or, in some cases, reverse atrial dilatation and left ventricular dysfunction. For these reasons, most clinicians focus initially on restoration and maintenance of sinus rhythm in patients with new-onset AF and opt for a rate-control strategy only when rhythm control fails.

However, several randomized controlled trials have demonstrated that a strategy aimed at restoring and maintaining sinus rhythm neither improves survival nor reduces the risk of stroke in patients with AF.

In the AFFIRM study (Atrial Fibrillation Follow-up Investigation of Rhythm Management), an insignificant trend toward increased mortality was noted in the rate control group, and importantly, no evidence suggested that the rhythm-control strategy protected patients from stroke. In the study, 4060 subjects aged 65 years or older whose AF was likely to be recurrent and who were at risk for stroke were randomized to a strategy of rhythm control (cardioversion to sinus rhythm plus drugs to maintain sinus rhythm) versus a strategy of rate control (in which no attempt was made to restore or maintain normal sinus rhythm).^[15] Clinically silent recurrences of AF in the rhythm-control group are theorized to be responsible for the increased rates of thromboembolic events and mortality noted in this cohort. This underscores the importance of anticoagulation in both rhythm-control and rate-control patients.

New developments aimed at curing AF are being explored actively. By reducing the critical mass required to sustain AF through either surgical or catheter-based compartmentalization of the atria (ie, MAZE procedure), fibrillatory wavelets collide with fixed anatomic obstacles, such as suture lines or complete lines of ablation, thus eliminating or reducing the development of permanent AF. One concern is that an extensive MAZE procedure can render the atrial severely hypocontractile, which may elevate the risk of embolic stroke even if AF is substantively suppressed. Some patients with focal origins of their AF also may be candidates for catheter ablation. Simple electric isolation of the origins of the pulmonary veins has proven roughly 80% successful in substantially reducing frequency and duration of AF in patients who do not tolerate AF well.

AF ablation methods continue to be studied and modified and thus may be considered as a work in progress rather than a mature primary therapy.Go to Catheter Ablation for complete information on this topic.

One of the major management decisions in AF (and atrial flutter) is determining the risk of stroke and appropriate anticoagulation regimen for low-, intermediate-, and high-risk patients. For each anticoagulant, the benefit in terms of stroke reduction must be weighed against the risk of serious bleeding.

Overall, approximately 15-25% of all strokes in the United States (75,000/y) can be attributed to AF. Known risk factors for stroke in patients with AF include male sex, valvular heart disease (rheumatic valvular disease), heart failure, hypertension, and diabetes. Additional risk factors, such as advanced age and prior history of stroke, diabetes, and hypertension, place patients with preexisting AF at even higher risk for further comorbidities such as stroke (see Table 1 below).^[25]

Table 1. Risk Factors for Stroke in Patients with Nonvalvular Atrial Fibrillation (Open Table in a new window)

Patients with rheumatic heart disease and AF have an even higher risk for stroke (17-fold). At least 4 large clinical trials have clearly demonstrated that anticoagulation with warfarin decreases the risk of stroke by 50-80%.

Most clinicians agree that the risk-benefit ratio of warfarin therapy in low-risk patients with AF is not advantageous. Warfarin therapy has, however, been shown to be beneficial in higher-risk patients with AF. A target international normalized ratio (INR) of 2-3 is traditionally used in this cohort, as this limits the risk of hemorrhage while providing protection against thrombus formation.

The appropriate treatment regimen for patients with AF at intermediate risk is controversial. In this population, the clinician should assess risk factors for thromboembolic disease, patient preference, risk of bleeding, risk of falls or trauma, and likelihood of medication adherence. Warfarin is also superior to clopidogrel or a combination of clopidogrel and aspirin in the prevention of embolic events in higher-risk patients.

Several risk factor assessment algorithms have been developed to aid the clinician on decisions on anticoagulation for patients with AF. The CHADS₂ index (Cardiac failure, Diabetes, Stroke [or S2 = transient ischemic attack]) is the most widely used of these algorithms.^[26] The CHADS₂ index uses a point system to determine yearly thromboembolic risk. Two points are assigned for a history of stroke or transient ischemic attack (TIA), and one point is given for age older than 75 years or a history of hypertension, diabetes, or heart failure.

The predictive value of this scoring system was evaluated in 1733 elderly patients with nonvalvular AF aged 65-95 years who were not given warfarin at hospital discharge. Although high scores were associated with an increased rate of stroke, few patients had a score greater than 5 or a score of 0 (see Table 2 below). However, the CHA2DS2-VASc (CHA2DS2-Vascular disease, Age 65-74 years, Sex category) score better predicts patients at high-risk as well as those categorized at low risk for thromboembolism.^[27]

Table 2. Adjusted Stroke Rate in Patients with Nonvalvular Atrial Fibrillation not Treated with Anticoagulation (Open Table in a new window)

Recommendations on anticoagulation for patients with nonvalvular AF are based on the 2006 American College of Cardiology (ACC)/American Heart Association (AHA)/European Society of Cardiology (ESC) task force guidelines on the management of patients with atrial fibrillation (see Table 3 below).^[25]

Table 3. Recommendations for Antithrombotic Therapy in Patients with Nonvalvular Atrial Fibrillation (Open Table in a new window)

High-risk factors include prior stroke, TIA, and systemic thromboembolism. Moderate-risk factors include age older than 75 years, hypertension, heart failure, left ventricular function less than 35%, and diabetes mellitus. Risk factors of unknown significance include female sex, age 65-74 years, coronary artery disease, and thyrotoxicosis.

The AFFIRM study and similar findings from the smaller Rate Control Versus Electrical Cardioversion (RACE) trial^[28] have led to the development of consensus guidelines that recommend an initial rate-control strategy for many asymptomatic patients with atrial fibrillation.

The ACC/AHA/ESC 2006 guidelines state that an initial rate-control strategy is "reasonable" for asymptomatic or minimally symptomatic older patients with hypertension and comorbid cardiovascular disease.^[25] These same guidelines state that for younger individuals, especially those without significant comorbid cardiovascular disease, an initial rhythm-control strategy may be a better approach.

Rate control

Regardless of the long-term management strategy chosen, control of ventricular rate is a critical component of management of new-onset AF. The main determinants of the ventricular rate during AF are those intrinsic and extrinsic factors that influence atrioventricular (AV) conduction. Foremost among these are the intrinsic AV nodal conduction properties. Underlying sympathetic and parasympathetic tone also influences AV nodal conduction. Rate-controlling agents act primarily by increasing AV nodal refractoriness.

Beta-blockers and calcium channel blockers are first-line agents for rate control in AF. These drugs can be administered either intravenously or orally. They are effective at rest and with exertion. Intravenous diltiazem or metoprolol are commonly used for AF with a rapid ventricular response. Caution should be exercised in patients with reactive airway disease who are given beta-blockers.

Digoxin can be used in the acute setting but does little to control the ventricular rate in active patients. As such, it is rarely used as monotherapy. Caution should be exercised in elderly patients and those with renal failure receiving digoxin. Digoxin is indicated in patients with heart failure and reduced LV function.

Amiodarone has a class IIa recommendation from the ACC/AHA/ESC for use as a rate-controlling agent for patients who are intolerant of or unresponsive to other agents, such as patients with CHF who may otherwise not tolerate diltiazem or metoprolol. Caution should be exercised in those who are not receiving anticoagulation, as amiodarone can promote cardioversion.

Extreme care must be taken in patients with preexcitation syndrome and AF. Blocking the AV node in some of these patients may lead to AF impulses that are transmitted exclusively down the accessory pathway, and this can result in ventricular fibrillation. (If this happens, the patient will require immediate defibrillation.) Calcium channel blockers and digoxin are contraindicated in these patients; flecainide or amiodarone can be used instead.^[29]

Anticoagulation

One of the most important considerations in the acute management of atrial fibrillation is the need for anticoagulation (see the image below). Acute cardioversion for AF carries a risk of thromboembolism unless anticoagulation therapy is initiated prior to the procedure and continued post procedure. Risk of thromboembolism is similar in patients undergoing either pharmacologic or electrical cardioversion. The risk of thromboembolic events is greatest when AF has been present for longer than 48 hours. TEE is a good predictor of acute risk. If no thrombus is seen in the cardiac chambers, particularly the left atrial appendage, and dense spontaneous echo contrast is not seen, cardioversion has low acute risk of stroke. Effective anticoagulation in patients with AF reduces the risk of stroke 3-fold after 4-6 weeks.

Patients with newly diagnosed AF and patients awaiting electrical cardioversion can be started on intravenous heparin (activated partial thromboplastin time [aPTT] of 45-60 seconds) or low-molecular-weight heparin (1 mg/kg bid).

Patients can be started concomitantly on warfarin in an inpatient setting while awaiting a therapeutic INR value (2-3). Many practices have developed specialized anticoagulation clinics to monitor INR values closely. Oral direct thrombin inhibitors may present an alternative to warfarin in a higher-risk population with nonvalvular AF.

Dabigatran (Pradaxa) is a newer oral anticoagulant that appears to be at least as effective as warfarin, with added expense but also added safety. Unlike warfarin, dabigatran does not require serial INR (PT) blood tests and is not significantly affected by almost any medication or vitamin (almost any pill can displace warfarin from serum albumen and thus increase the INR).

Several scoring systems have been developed to estimate risk-benefit for warfarin use in AF (summarized below). The BAFTA trial suggests the risk of thromboembolism is underestimated in individuals older than 75 years, with the further suggesting that all patients older than 75 years with episodes of AF lasting longer than 24 hours should be considered for anticoagulation. In the highest-risk population (eg, AF with valvular heart disease or prior embolic cerebrovascular accident), bridging anticoagulation with heparins may be required in the periprocedural period.

The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study demonstrated that a 5-point risk stratification scheme (ie, anemia, severe renal disease, age, prior bleeding, and hypertension) was effective in quantifying the risk for major hemorrhage among patients with AF receiving warfarin.^[30]

Another new anticoagulant, rivaroxaban (Xarelto), was approved by the US Food and Drug Administration (FDA) in November 2011 for nonvalvular AF.^[31] It is a highly selective direct Factor Xa inhibitor with oral bioavailability, with rapid onset of action. Clinical trial data have shown that it allows predictable anticoagulation with no need for dose adjustments and routine coagulation monitoring.^[32]

Approval of Xarelto was based on the ROCKET AF multicenter trial. The multinational, double-blind study included over 14,000 patients who were randomized to either rivaroxaban or warfarin. In the primary analysis of this study (n=429), rivaroxaban was found to be noninferior to warfarin for prevention of stroke or systemic embolism in patients with nonvalvular AF. A significant difference was observed for intracranial hemorrhage and fatal bleeding with rivaroxaban compared with warfarin.^[33] During the approval process, concern was expressed over the amount of time the warfarin-treated patients spent at the optimal INR during the study (57.8%), which was lower than in other trials with warfarin (eg, RE-LY trial for dabigatran).^[34]

Cardioversion

Cardioversion may be performed electively or emergently to restore sinus rhythm in patients with new-onset atrial fibrillation. Cardioversion is most successful when initiated within 7 days after onset of AF. The need for cardioversion may be acute when AF is responsible for hypotension, heart failure, or angina.

Pharmacologic agents or direct current energy can be used to cardiovert patients with AF. Pharmacologic cardioversion has the advantage of not requiring sedation or anesthesia, but the major disadvantage is the risk of ventricular tachycardia and other serious arrhythmias.

Long-term management of atrial fibrillation is focused on reducing the likelihood of AF recurrence, reducing AF-related symptoms, control of ventricular rate, and reducing stroke risk. As discussed previously, AF is often the result of established cardiovascular risk factors. Appropriate management of these risk factors will reduce the likelihood of future episodes of AF and AF-related morbidity and mortality. Anticoagulation with either aspirin or warfarin should be initiated for all individuals with AF, except those with lone AF or contraindications. Selection of the appropriate antithrombotic regimen for a given patient should be balanced between the risk of stroke and the risk of bleeding. Antiarrhythmic therapy can aid in maintenance of sinus rhythm in certain patients but requires close monitoring.

Optimal long-term strategies for AF management should be based on a thoroughly integrated consideration of patient-specific factors and likelihood of success. As a rule, younger patients with more severe symptoms and fewer comorbidities tend to derive greater benefit from a long-term focus on rhythm control. Older patients with structural heart disease (eg, left ventricular hypertrophy, prior MI, depressed ejection fraction, atrial dilation) are less likely to remain in sinus rhythm and are more likely to have serious side effects from antiarrhythmic drugs. In this cohort, most clinicians focus on long-term rate control.

Because of the electrophysiologic and structural remodeling caused by AF, many patients with paroxysmal AF will progress to persistent and permanent AF. The degree to which this reflects the continuing influence of underlying cardiovascular risk factors as opposed to a direct effect of AF is unknown. Regardless, clinicians need to reevaluate their management strategies frequently, as AF burden and comorbidities increase with time.

Anticoagulation

The goal of long-term anticoagulation in atrial fibrillation is to reduce the risk of thromboembolism. Patients in AF have a risk of stroke or peripheral embolism that is approximately 5 times that of individuals in sinus rhythm. Recommendations for anticoagulation for patients with nonvalvular AF are based on guidelines from a 2006 ACC/AHA/ESC task force on the management of patients with atrial fibrillation.^[2]

Anticoagulation therapy with warfarin is significantly more effective than antiplatelet therapy (relative risk of 40%) if the INR is adjusted. The INR goal in AF is usually between 2 and 3, except in patients who are at a significant risk for stroke (eg, patients with artificial valves, those with rheumatic heart disease, and those at a high risk for AF with recurrent prior strokes), in whom the INR should be maintained between 2.5 and 3.5. A lower INR goal (1.8-2) may be considered in elderly patients who are at high risk for a fall.

Anticoagulation clinics have shown more success and a lower complication rate than primary care physicians in controlling patients’ INR. In addition, one study reported that patients who used an Internet-based program for patient self-management of oral anticoagulant therapy achieved a higher mean time in the therapeutic range than patients whose INR was controlled by an established anticoagulation clinic.^[35] Similar programs alone or in combination with regular care provided by anticoagulation clinics may improve the mean time that patients are in the therapeutic range and may further reduce the risk of stroke.

As patients with AF age, the relative efficacy of oral anticoagulation appears not to decrease, whereas the efficacy of antiplatelet therapy does appear to decrease, according to a study by van Walraven.^[36]

Several scoring systems have been developed to estimate risk-benefit for Coumadin use in AF (summarized below). The BAFTA trial suggests the risk of thromboembolism is underestimated in individuals older than 75 years, with the further suggesting that all patients older than 75 years with episodes of AF lasting longer than 24 hours should be considered for anticoagulation.

The major adverse effect of anticoagulation therapy with warfarin is bleeding. Factors that increase this risk include the following:

• History of bleeding (the strongest predictive risk factor)
• Age older than 75 years
• Liver or renal disease
• Malignancy
• Thrombocytopenia or aspirin use
• Hypertension
• Diabetes mellitus
• Anemia
• Prior stroke
• Fall risk
• Genetic predisposition
• Supratherapeutic INR

Several risk models have been introduced. The risk model called HEMORR2HAGES assigns points to risk factors, as follows^[37] :

• History of bleeding (2 points)
• Hepatic or renal disease (1 point)
• Alcohol abuse (1 point)
• Malignancy (1 point)
• Older age (>75 y) (1 point)
• Reduced platelet count or function, including aspirin therapy (1 point)
• Hypertension (1 point)
• Anemia (1 point)
• Genetic predisposition (1 point)
• Excessive fall risk (1 point)
• Stroke (1 point)

Using this scoring, the risks of a major bleeding event per 100 patient-years of warfarin therapy are as follows:

• 0 points - 1.9%
• 1 point - 2.5%
• 2 points - 5.3%
• 3 points - 8.4%
• 4 points - 10.4%
• 5 or more points - 12.3%

When the bleeding risk outweighs the benefit, avoidance of anticoagulation therapy in AF should be considered. In addition, because of its teratogenic effects, anticoagulation with warfarin is contraindicated in pregnant women, especially in the first trimester.

According to the 2011 update to ACCF/AHA/HRS guidelines on atrial fibrillation, if warfarin will not be used, adding clopidogrel to aspirin may be considered.^[38]

The RE-LY study evaluated the efficacy and safety of 2 different doses of dabigatran relative to warfarin in more than 18,000 patients with atrial fibrillation. Patients were randomized to 1 of 3 arms: (1) adjusted dose warfarin, (2) dabigatran 110 mg bid, or (3) dabigatran 150 mg bid. Dabigatran 110 mg was noninferior to warfarin for the primary efficacy endpoint of stroke or systemic embolization, while dabigatran 150 mg was significantly more effective than warfarin or dabigatran 110 mg. Major bleeding occurred significantly less often with dabigatran 110 mg than warfarin; dabigatran 150 mg had similar bleeding to warfarin.^{[39, 34]}

A meta-analysis by Uchino and Hernandez evaluated the risk of myocardial infarction or acute coronary syndrome (ACS) with the use of dabigatran. The results suggest the risk of myocardial infarction or ACS was similar when using revised RE-LY trial results. Dabigatran is associated with an increased risk of myocardial infarction or ACS in an extensive range of patients when tested against different controls.^[40]

Guidelines from the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS) on atrial fibrillation have been updated to include the use of oral direct thrombin inhibitors (ie, dabigatran).^[41] The guidelines include a class Ib recommendation (ie, treatment is useful/effective based on a single randomized trial) for dabigatran.

The guidelines recommend dabigatran may be used as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal-to-permanent atrial fibrillation and risk factors for stroke or systemic embolization. Patients with atrial fibrillation who are not candidates include those with prosthetic heart valves or hemodynamically significant valve disease, severe renal failure (creatinine clearance ≤15 mL/min), or advanced liver disease.

Anticoagulation prior to and during an elective surgery may be continued or stopped depending on the patient’s risk of bleeding and risk of thromboembolism. If the risk of thromboembolism is high (stratified by the CHADS₂ score) and the risk of bleeding is low, anticoagulation should be continued with the INR in the low therapeutic range. However, a high risk of bleeding during the procedure should prompt discontinuation of warfarin for 3-5 days prior to surgery. These patients should then be treated with heparin prior to and following the operation to allow discontinuation of anticoagulation if bleeding occurs.

In general, patients who develop AF only postoperatively do not need anticoagulation. Administration of preoperative and postoperative beta-blockers is usually sufficient, as postoperative AF is usually paroxysmal and tends to terminate spontaneously. The Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) Atrial Fibrillation Substudy found that the administering of colchicine appears to be safe and efficacious in the reduction of postoperative AF, which could potentially halve the complication and reduce the time a patient stays in the hospital.^[42]

A mutation in coagulation factor IX may cause spontaneous bleeding even with INR in the therapeutic range. Adverse effects of warfarin therapy are not limited to bleeding, however; other important side effects include skin necrosis within the first few days of therapy and cholesterol embolization to the skin or visceral organs in the first few weeks of therapy.

A large cohort study in Denmark compared bleeding risk of anticoagulants prescribed upon hospital discharge for atrial fibrillation. During mean follow-up (3.3 y), 11.4% of patients experienced a nonfatal or fatal bleeding episode. The highest incidence for bleeding was observed for dual therapy with warfarin and clopidogrel and for triple therapy with warfarin, aspirin, and clopidogrel (3-fold higher risk) compared with single agent use.^[43]

Omega-3 fatty acids

Several small trials have suggested that treatment for paroxysmal AF with prescription omega-3 fatty acids may provide a safe and effective treatment option. However, no benefit has been found to date.^{[44, 45]}

Angiotensin converting enzyme (ACE) inhibitors and ACE receptor blockers (ARB)

Trials examining the incidence of AF in patients with heart failure who are treated with ACE inhibitors or ARBs have demonstrated a potential beneficial effect on AF recurrence. This recurrence is thought to be mediated by blocking the rennin-angiotensin-aldosterone system and the downstream effects on atrial mechanical and electrical remodeling.^{[46, 47, 48]}

A study by Yusuf et al examined the effects of irbesartan in patients with permanent AF or at least 2 episodes of paroxysmal AF in the previous 6 months.^[49] Irbesartan did not demonstrate a benefit in patients with AF who were already receiving an ACE inhibitor or patients in sinus rhythm. No reduction in cardiovascular death, stroke, or myocardial infarction was noted in the patient population studied.

Rate control

As discussed previously, several trials have validated the noninferiority of an initial rate-control strategy. Many clinicians believe, however, that an attempt at a rhythm-control strategy should be made in most patients. Older patients with comorbid cardiovascular disease have a lower likelihood of successful long-term rhythm control, and thus, these patients are often managed using a rate-control strategy. Some patients managed initially with a rhythm-control strategy will progress to recurrent or persistent AF. Clinicians often switch to a rate-control strategy as the AF burden increases.

Effectiveness of rate control should be assessed both at rest and with exertion, especially in patients who experience primarily exertional AF-related symptoms. Twenty-four hour Holter monitoring or exercise-treadmill testing can be helpful in evaluating heart rate variability.

Adequate rate control was previously defined as a heart rate of 60-80 bpm at rest and 90-115 bpm with moderate exercise. However, ACCF/AHA/HRS guidelines on management of atrial fibrillation were updated in 2011 to state that there was no benefit in achieving strict heart rate control (< 80 bpm at rest, < 110 bpm after a 6-minute walk) relative to more lenient rate control (< 110 bpm at rest). Strict rate control in patients with stable ventricular function is no longer recommended.^[38]

AV nodal blocking medications are the cornerstone of rate control in long-standing AF. In the absence of an accessory pathway, oral beta-blockers, nondihydropyridine calcium channel blockers, and digoxin are effective. Generally, coadministration of beta-blockers and calcium channel blockers is reserved for patients in whom adequate rate control cannot be achieved with a single agent.

Digoxin can be effective in sedentary patients (especially in those with heart failure) but requires close monitoring of drug levels and renal function. Combinations of rate-control medications (eg, beta-blocker and digoxin) may be superior to individual agents in some patients.

Amiodarone may contribute to ventricular rate control. On the other hand, antiarrhythmic agents may organize AF to a potentially life-threatening atrial flutter with 1:1 AV conduction. Particularly with class IC agents, maintenance of effective AV nodal rate control is essential in most patients. Therefore, administration of a beta-blocker or calcium channel blocker is recommended before class IC drugs are initiated.

In the presence of tachycardia-mediated cardiomyopathy or inadequate ventricular rate control despite drug therapy, AV nodal ablation and pacemaker implantation may be considered.

Rhythm control

Maintenance of sinus rhythm requires treatment of cardiovascular risk factors and any underlying disorder (ie, hyperthyroidism) that may have triggered AF. As mentioned previously, several antiarrhythmic drugs (flecainide, propafenone, dofetilide, amiodarone) have established efficacy in the pharmacologic conversion of AF to sinus rhythm. The noncardiac adverse effects and contraindications of each drug should be checked prior to administration.

Amiodarone, as a part of a strategy to achieve sinus rhythm, appears to be safe and effective in patients with persistent AF, according to Doyle and Ho. However, in their study, intolerable adverse effects were more common with amiodarone than with placebo or rate-control drugs.^[50] Nevertheless, in patients with cardiac disease such as coronary artery disease or systolic or diastolic heart failure, amiodarone becomes the drug of choice because of its decreased proarrhythmic effects compared with other antiarrhythmic drugs.^[29]

Amiodarone was also found to be more effective at maintaining sinus rhythm than other drugs in the Canadian Trial of Atrial Fibrillation (CTAF) and the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T).^{[51, 52]}

The 2011 update to the ACCF/AHA/HRS AF guideline adds that it is reasonable to use dronedarone to reduce the probability that hospitalization will be required for patients with paroxysmal AF or after conversion of persistent AF. Class IV heart failure or a recent episode of decompensated heart failure are contraindications.^[38] Dronedarone is not approved for permanent atrial fibrillation.

Dronedarone was found to be associated with increased mortality in patients with permanent atrial fibrillation. A recent randomized, double-blind, phase III trial, the Permanent Atrial fibriLLation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study, was halted following a preliminary review that revealed that dronedarone was associated with a 2-fold rise in risk of death. Two-fold increases in 2 other endpoints, stroke and hospitalization for heart failure, were also noted when compared with placebo. Healthcare professionals are advised by the FDA not to prescribe dronedarone to patients with permanent atrial fibrillation. The FDA is currently analyzing whether the PALLAS results apply to patients taking dronedarone for paroxysmal or persistent atrial fibrillation and atrial flutter. The study results are considered preliminary at this time because the data have not undergone quality assurance procedures and have not been completely adjudicated.^[53]

A separate study by Connolly et al also found that dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events; the authors of that study suggest that dronedarone should not be used in this group of patients.^[54]

Several distinct agents, most notably sotalol, are used for the long-term maintenance of sinus rhythm. Sotalol is efficacious, but as with other class III drugs, it requires close monitoring of the QT interval and serum electrolytes. Sotalol is associated with the risk of QT interval prolongation and torsade de pointes. The proarrhythmic effect of sotalol is increased in patients with CHF (unlike dofetilide and amiodarone), so it is generally contraindicated in such patients or in those with a prolonged QT interval. Hypokalemia should be corrected and monitored prior to administration of sotalol because it may also prolong the QT interval. Sotalol can be used in patients with coronary artery disease.^[29]

Class III agents (sotalol, amiodarone) also have some beta-blocking effect and should be used with caution in patients with a history of bradycardia.

Class Ic drugs increased the mortality risk in patients with coronary artery disease during the Cardiac Arrhythmia Suppression Trial (CAST) and therefore should not be used in these patients.^[55]

Class Ic drugs increased the mortality risk in patients with coronary artery disease during the Cardiac Arrhythmia Suppression Trial (CAST) and therefore should not be used in these patients.^[51]

Catheter ablation performed in experienced centers is recommended in the 2011 update to the ACCF/AHA/HRS AF guidelines for several indications:{Ref55}

• It is recommended as an alternative to pharmacologic therapy to prevent recurrent paroxysmal AF in significantly symptomatic patients with little or no structural heart disease^[52] or severe pulmonary disease (Class I, evidence level A).
• It is reasonable as a treatment for symptomatic persistent AF.
• Catheter ablation may be reasonable as a treatment for symptomatic paroxysmal AF in patients with some structural heart disease.

An assessment by Hoyt et al of all patients undergoing AF ablation at Johns Hopkins Hospital between February 2001 and December 2010 found that the complication rate of catheter ablation of AF decreased with increased institutional experience.^[56]

Surgical ablation of AF is also an option for patients with AF undergoing other cardiac surgery and for those patients in whom pharmacologic and catheter-based procedures are ineffective or contraindicated. Atrial fibrillation ablation may be superior to AV nodal ablation and biventricular pacing in heart failure patients but is technically difficult and demanding, and the widespread applicability of ablation in this population of patients is uncertain.

In the first randomized clinical trial comparing the efficacy and safety of catheter ablation versus minimally invasive surgical ablation during a 12-month follow-up, Boersma et al found that patients with AF who had a dilated left atrium and hypertension or who failed prior AF catheter ablation, surgical ablation was superior in achieving freedom from left atrial arrhythmias after 12 months of follow-up; however, the procedural adverse event rate was found to be significantly higher with surgical ablation than for catheter ablation, primarily postoperative pneumothorax, major bleeding, and an increased need for permanent pacing.^[57]

Go to Catheter Ablation for complete information on this topic.

New medical and device-based rhythm-control therapies are being explored actively. Experimental and clinical data suggest that renin-angiotensin system (RAS) antagonists and HMG-CoA-reductase inhibitors (statins) may decrease the incidence of AF and increase the likelihood of successful cardioversion.^{[58, 59, 60, 61]} Device-based therapies under investigation include single- and dual-site atrial pacemakers to prevent AF, as well as atrial defibrillators to rapidly restore sinus rhythm. Invasive (surgical and catheter-based) therapies to compartmentalize the atria and localize focal triggers (in the pulmonary veins) are being evaluated and refined. (See Surgical Care.)

Electrical cardioversion

Patients who are hemodynamically unstable, who have severe dyspnea or chest pain with atrial fibrillation, or who have preexcited atrial fibrillation should undergo urgent cardioversion.^[29] In stable patients with symptomatic new-onset AF, the rate-control strategy may be considered first to control the ventricular rate. If rate-control treatment does not elicit a response or if echocardiography does not reveal any valvular or functional abnormality of the heart, cardioversion is indicated.

DC cardioversion is the delivery of electrical current that is synchronized to the QRS complexes; it can be delivered in monophasic or biphasic waveforms. The required energy for cardioversion is usually 100-200 J (sometimes higher energy is required) for monophasic waveforms and less for biphasic waveforms. The patient should be sedated. In patients with AF of relatively short duration in whom the left atrium is not significantly large, the success rate of cardioversion exceeds 75% (ie, the size of the left atrium and the duration of AF inversely correlate with the success rate of cardioversion).

Embolization is the most important complication of cardioversion. Accordingly, thrombus in the heart should be ruled out with transesophageal echocardiography, or warfarin should be given for anticoagulation for 4 weeks before cardioversion is performed. Stunning of the atria and stasis can occur after cardioversion, and this can lead to thrombus formation even though the patient is in sinus rhythm. Therefore, the patient should receive anticoagulants for at least 4 weeks following the procedure.

Other complications of electrical cardioversion may include pulmonary edema, hypotension, myocardial dysfunction, and skin burns, which may be avoided with the use of steroid cream and proper technique. Electrical cardioversion is also associated with some ST- and T-wave changes on ECG and may elevate levels of serum cardiac biomarkers. Synchronization prevents serious ventricular arrhythmias.

Placement of pads or paddle positions include anterior-lateral (ventricular apex and right infraclavicular) and anterior-posterior (sternum and left scapular), with at least one study suggesting increased efficacy with the anterior-posterior (AP) method.

Biphasic waveforms are proved to convert AF at lower energies and higher rates than monophasic waveforms. Strategies include dose escalation (70, 120, 150, 170J for biphasic or 100, 200, 300, 360J for monophasic) versus beginning with single high energy/highest success rate for single shock delivered. Patients who are stable and/or awake and can tolerate sedation should be pretreated, with typical regimens involving midazolam, fentanyl, and propofol.

Cardioversion of patients with implanted pacemakers and defibrillator devices is safe when appropriate precautions are taken. Keeping the cardioversion pads in an AP orientation ensures that the shocks are not directly over the generator. Alteration in pacer-programmed data has been reported, as well as heart block and elevated enzymes if the current is conducted through a pacer lead.

Pharmacologic cardioversion

Although pharmacologic cardioversion may be used as the first-line strategy, it is used mainly if DC cardioversion fails or, in some cases, as a precardioversion strategy.

Out-of-hospital self-administration of either flecainide 300 mg or propafenone 600 mg (weight-based dosages if >70 kg) was determined to be successful in terminating AF in 94% of episodes (mean time to symptom resolution of 133 minutes) by Alboni et al. The investigators studied outpatient treatment of atrial fibrillation with a “pill-in-the-pocket” approach in 268 patients with little or no structural heart disease presenting to the emergency department with symptomatic AF.^[62]

Pretreatment with amiodarone, flecainide, ibutilide, propafenone, or sotalol has been shown to increase the success rate of DC cardioversion and is recommended by the American College of Cardiology.^[2] This strategy is also recommended when DC cardioversion fails and prior to repeat DC cardioversion.^[2] Intravenous amiodarone is typically given as a 150-mg bolus over 10-15 minutes, followed by a continuous infusion of 1 mg/min for 6 hours and then 0.5 mg/min.

Hemodynamically unstable patients (eg, those with hypotension) may not tolerate antiarrhythmic drugs, and the adverse effects and contraindications of each antiarrhythmic drug should be considered carefully before administration. Because of possible proarrhythmic adverse effects of antiarrhythmic drugs, these patients should be monitored for at least 24 hours, requiring hospitalization in most cases.

The ACC/AHA/ESC guidelines provide the following recommendations regarding pharmacologic conversion of atrial fibrillation^[63] :

• For conversion of AF of 7 days or less, agents with proven efficacy include dofetilide, flecainide, ibutilide, propafenone, and, to a lesser degree, amiodarone and quinidine; less effective or incompletely studied agents include procainamide, digoxin, and sotalol.
• For conversion of AF lasting 7-90 days, agents with proven efficacy include dofetilide, amiodarone, ibutilide, flecainide, propafenone, and quinidine; less effective or incompletely studied agents include procainamide, sotalol, and digoxin.
• For conversion of AF lasting more than 90 days, oral propafenone, amiodarone, and dofetilide have been shown to be effective at converting persistent AF to normal sinus rhythm (NSR).

The US Food and Drug Administration (FDA) mandates inpatient monitoring for dofetilide initiation. Patients who start sotalol usually require inpatient monitoring (for torsade de pointes), although patients with no heart disease, with a QT interval less than 450 msec, and with normal electrolytes should be started on outpatient medications.

In 2010, the American Heart Association-American Stroke Association (AHA-ASA) issued its guidelines for the primary prevention of stroke, which included the note that screening patients over 65 years of age for AF in the primary care settings using pulse taking followed by an ECG may be useful. Adjusted-dose warfarin should be used for all patients with nonvalvular AF (target INR 2-3). Aspirin is recommended for low and moderate-risk patients with AF and for high-risk patients unsuitable for anticoagulation; a combination of clopidogrel and aspirin may protection against stroke than aspirin alone.^[64]

Special considerations

Postoperative AF is common, and perioperative beta blockers are recommended in all patients undergoing cardiac surgery unless contraindicated.^[65] Preoperative administration of amiodarone and sotalol may reduce the incidence of AF in patients undergoing cardiac surgery. As such, these agents may be used as prophylactic therapy in those at high risk for postoperative AF.

Postoperative AF was reduced by treatment with Landiolol hydrochloride.^[66] Amelioration of ischemia, an anti-inflammatory effect, and inhibition of sympathetic hypertonia by Landiolol presumably reduced the occurrence of AF. Hypotension or bradycardia did not develop in any of the patients, indicating the safety of this beta-blocker. These findings suggest that Landiolol hydrochloride could be useful in the perioperative management of patients undergoing cardiac surgery.

Retrospective data suggest that atrial-based pacing (AAI, DDD modes) reduces the risk of developing AF and increases the interval between episodes in patients with sick sinus syndrome.^[67]

The goal of catheter ablation and surgical treatment of atrial fibrillation is to disconnect triggers and/or to modify the substrate for AF. Mapping and radiofrequency (RF) ablation of AF is one of the most complex ablation procedures. Numerous approaches are used depending on the expertise of the cardiac electrophysiologist and characteristics of the AF.

Paroxysmal AF is usually caused by triggered and ectopic activity in pulmonary veins, and ablation around the veins terminates the arrhythmia. In persistent AF, triggering foci and reentry circuits may coexist in the atrial tissue, requiring more extensive mapping and ablation to terminate the AF; this yields a lower success rate than ablation used to treat paroxysmal AF.

Aniarrhythimic drug (AAD) treatment for 6 weeks after ablation of paroxysmal AF was shown to be well tolerated, to reduce the incidence of clinically significant atrial arrhythmias, and to reduce the need for cardioversion or hospital admission during that period, according to Roux et al. Class IC drugs were used as the first line of therapy, and sotalol was the most commonly used drug in cases of LV dysfunction or CAD. Measured outcomes included atrial arrhythmias lasting more than 24 hours; atrial arrhythmias associated with severe symptoms that required hospitalization, cardioversion, or initiation/change of antiarrhythmic drug therapy; and intolerance to antiarrhythmic agent requiring drug cessation.^[68]

Hussein et al performed a registry study that examined controls and patients with mitral valve replacement who underwent AF ablation. No cases of catheter entrapment or stroke were reported. Although most patients required more than one ablation, at last follow-up, 69% were arrhythmia-free and no longer taking antiarrhythmic medications. This provides evidence that AF ablation is safe in this group of patients. Of note, many patients had flutter and creation of a flutter line was one of the keys to success.^[69]

Two approaches to compartmentalization of the atria are surgical, by which multiple cuts are made to the atria, and radiofrequency ablation.

Surgical compartmentalization of the atria (maze procedure)

Since its inception, surgical compartmentalization of the atria, or the “maze” procedure, has evolved as an exciting approach with the potential to cure atrial fibrillation. The procedure involves making a series of small endocardial incisions in the right and left atria to isolate the pulmonary veins and interrupt potential reentrant pathways required for AF maintenance. Early experience showed that atrial transport is restored postoperatively and that long-term anticoagulation is not required.

The downside remains the need for an open chest procedure; however, thoracoscopic procedures may reduce hospitalization and recovery times in the future. The maze procedure remains an attractive procedure for patients with AF who are undergoing concomitant mitral valve procedures. Its role as a primary therapy for AF is doubtful. The role of lesion sets on outcome after maze procedure was studied; the addition of right-sided ablation was found to improve clinical and electrophysiologic results after maze procedure.^[70]

Compartmentalization of the atria with continuous ablation lines of blockage

As a parallel to the maze procedure, electrophysiologists are attempting to mimic surgical suture lines with radiofrequency lesions. The procedures tend to last many hours, and success rates are somewhat disappointing (50-60%), with the occurrence of left atrial reentrant tachycardias and left atrial flutters (requiring further ablation procedures).^[71]

Researchers are unsure which areas of the atria are necessary to sustain AF. Purely right-sided lesions are not sufficient to eliminate AF, making left atrial procedures necessary. In addition, gaps in linear lesions can be difficult to find.

Research currently focuses on catheter design to deliver linear continuous lesions. Additionally, alternative energy sources (eg, cryotherapy, laser, ultrasound) may improve the ability to deliver transmural lesions in the left atrium.

In some patients, AF appears to be triggered by electrically active pulmonary vein foci.^[72] These patients typically have an abundance of ectopic atrial beats noted on 24-hour Holter monitoring. Electrical isolation of individual pulmonary veins, and thus the ectopic foci, is performed successfully at many centers, and patient selection is key to success.

A combined procedure including individual pulmonary vein isolation, as well as left atrial ablation (ie, encircling pulmonary vein pairs, connecting right and left pairs along the left atrial roof, and connection to the mitral valve annulus), is often necessary. Chest CT or MRI can be used to recreate 3-dimensional anatomy in the left atrium, thus aiding in mapping and creating contiguous lines in the left atrium, as displayed in the video below.

The AF cure rate after pulmonary vein isolation may be influenced by sinus node function in both the early and late stages. Although further examinations are required, pulmonary vein isolation may be an adequate treatment for persistent/permanent AF in patients with normal sinus node function.^[73]

Patients with paroxysmal AF in whom antiarrhythmic drug therapy does not elicit a response are potential candidates for RF ablation of AF. The threshold for catheter ablation has fallen over the years and is likely to continue to fall. Ablation of persistent AF is more complex and yields lower success rates. Therefore, RF ablation is an option only if antiarrhythmic drugs fail in patients with persistent AF who remain severely symptomatic despite adequate ventricular rate control.^[74]

The success rate of RF ablation in the treatment of AF varies depending on the type and duration of AF (ie, paroxysmal vs persistent), structural remodeling of the heart, and the technique and expertise of the cardiac electrophysiologist, but it usually ranges from 60-80% over 1-2 years of follow-up.

Patients opting for AF ablation should be told to expect to undergo repeat ablations because they are not uncommon and they improve overall success.^[75]

Complications associated with RF ablation of AF include cardiac perforation, pericardial effusion, cardiac tamponade, vascular access complications, pulmonary vein stenosis, thromboembolism, atrioesophageal fistula, and left atrial flutter. Pulmonary vein stenosis develops in about 6% of patients and may cause dyspnea, chest pain, cough, and hemoptysis.^[2] If pulmonary vein stenosis is suspected following RF ablation, further diagnostic workup with TEE, spiral CT scanning, or MRI is recommended. MRI is the most accurate test in diagnosing this complication. Patients with pulmonary vein stenosis should undergo percutaneous angioplasty, which can significantly improve pulmonary blood flow and the patient's symptoms.

Go to Catheter Ablation for complete information on this topic.

AV node ablation may be an alternative in patients with persistent AF and an uncontrolled ventricular response despite aggressive medical therapy. Catheter ablation of the AV junction permanently interrupts conduction from the atria to the ventricles.

Because the result is permanent AV block, a permanent ventricular pacemaker is required. AF may still be present, but the pacemaker governs the ventricular response. The risk of thromboembolism is unchanged, and patients still require anticoagulation; however, most patients are relieved of their symptoms. During the first 1-3 months, the pacing rate must be programmed in the 80- to 90-beat range to prevent torsade de pointes, which presumably occurs because of slow ventricular rates and early after-depolarizations. In patients with significant ventricular dysfunction and permanent ventricular pacing, a biventricular device may be appropriate.^[76] Improvements in LV size and function, functional class, and quality-of-life scores have been demonstrated.^[77]

Embolic stroke in patients with nonvalvular AF is thought to be associated with left atrial appendage (LAA) thrombi. LAA closure may be a suitable alternative to chronic warfarin therapy for stroke prophylaxis in patients with nonvalvular AF, according to Holmes and colleagues. The investigators compared the efficacy and safety of LAA percutaneous closure with warfarin therapy in patients with AF, and follow-up at the point of 1065 patient-years showed the intervention group (LAA closure without warfarin treatment) event rate was 3 per 100 patient-years compared with the control group (patients given warfarin) event rate of 4.9 per 100 patient-years.^[78]

Consultation with a cardiac electrophysiologist or knowledgeable clinician is recommended prior to antiarrhythmic drug initiation.

A cardiologist may be consulted emergently if complicating factors are present or if the patient is experiencing ongoing cardiac ischemia or infarction not treatable with DC cardioversion, rate-reduction measures, and standard chest pain protocols.^[79] A patient with acute myocardial infarction (AMI) and new-onset AF who is stable may benefit from simple rate-control measures (eg, intravenous beta-blockers) while being prepared for the catheterization laboratory and while intravenous nitrates, heparin, and aspirin are begun. In the patient with an ST elevation MI, the main emphasis, however, is to minimize door-to-open-artery time.

A patient's cardiologist plays a vital role in determining the most appropriate long-term strategy for a patient with AF and provides crucial follow-up care.

RF ablation of atrial fibrillation

Patients who undergo RF ablation of atrial fibrillation should be monitored for the signs and symptoms of potential complications, such as the following:

• Cardiac perforation
• Pericardial effusion
• Cardiac tamponade
• Vascular access complications
• Pulmonary vein stenosis
• Thromboembolism
• Atrioesophageal fistula
• Left atrial flutter

In addition, AF can recur and most episodes are asymptomatic. Therefore, it is important to monitor for signs and symptoms of recurrent AF in follow-up visits and to administer appropriate diagnostic tests if recurrence is suspected.

Further outpatient care

Assessment and reassessment of thromboembolic risk is necessary, and periodic ECG monitoring (especially when taking antiarrhythmics) and Holter monitoring are often necessary to assess for paroxysmal AF and/or rate control.

Deterrence/prevention

Experimental and clinical data suggest that renin-angiotensin system (RAS) antagonists and HMG-CoA reductase inhibitors (statins) may decrease the incidence of AF and increase the likelihood of successful cardioversion.^{[58, 59, 60, 61]}

In addition, treatment of underlying cardiovascular risk factors such as hypertension, CAD, valvular heart disease, obesity, sleep apnea, diabetes, and heart failure is likely to decrease the incidence of AF. Fish oil preparations have also been shown to reduce ventricular arrhythmias in at-risk populations (CAD) and may also protect against AF.