Overview and Classification
AF is a chaotic atrial rhythm related to continuous and variable acti- vation of the atria. There are no distinct P waves or periods of atrial quiescence. It is characterized electrocardiographically by a wavering baseline associated with an irregular ventricular response (see Fig.
9.6D).
AF is the most common clinically significant arrhythmia. It affects 2.2 million people in the United States. Its prevalence is between 0.4%
and 1% in the general population, and it increases with age, reaching 8% in those older than 80 years. Patients with AF have a higher risk of stroke, heart failure, and mortality. However, the role of AF as an inde- pendent determinant of mortality is uncertain because it commonly coexists with other important conditions. Patients with lone AF do not have an increased mortality rate, and carefully designed trials exploring the benefit of maintenance of sinus rhythm over rate control show, in most populations, no survival benefit for sinus rhythm. One exception may be in patients with systolic heart failure in addition to AF where ablation of AF may have a survival advantage. The recently completed CASTLE-AF (Catheter Ablation vs. Standard Conventional Treatment in Patients with LV Dysfunction and AF) showed a significant reduc- tion in mortality with catheter ablation of AF in this select population.
AF is often classified by its clinical presentation and pattern. When AF is first detected, it is called new onset, and its ultimate pattern is ini- tially undetermined. When AF relapses during follow-up, it is called recurrent and classified by its clinical pattern. If AF terminates sponta- neously, it is called paroxysmal AF. Although episodes lasting up to 7 days are defined as paroxysmal, most episodes of paroxysmal AF ter- minate within the first 24 hours and many terminate within minutes or hours of onset. When AF lasts longer than 7 days, it is designated as persistent. AF that persists for a long interval, typically more than a year, without return of an interim period of sinus rhythm (sponta- neously or as a result of medical intervention such as cardioversion) is termed long-standing persistent AF. Finally, when a clinical decision is made to no longer try to maintain sinus rhythm, the term permanent AF is used.
Mechanisms of Atrial Fibrillation
Because of its chaotic nature, it has been difficult to study AF, and its mechanisms remain incompletely understood. The initiation of spon- taneous AF is a consequence of rapid electrical firing from preferential focal sites of origin. The most common site of focal origin is from left atrial muscle sleeves extending along the outer surface of the pulmo- nary veins. When firing does not originate from a pulmonary vein, it is commonly from the left atrial tissue immediately adjacent to one of the veins or occasionally from one of the other thoracic veins such as the ostium of the superior vena cava or the ostium of the coronary sinus. Atrial rates recorded in and around the pulmonary veins are sig- nificantly higher than at other atrial sites, suggesting that activity in the region of the veins is important in perpetuating AF after initiation.
These insights have produced highly effective techniques for the cure of AF. Ablation techniques designed to isolate these trigger sites from the atrium have success rates of 70% to 80% for the cure of
paroxysmal AF and somewhat lower rates for the cure of persistent AF.
Ablation restricted to the region of the pulmonary veins and adjacent left atrium is curative in most patients with AF, implying that most cases of AF are arrhythmias entirely contained within and maintained by the left atrium and connecting veins. In the same way that typical atrial flutter is the characteristic arrhythmia of the right atrium, AF is the characteristic arrhythmia of the left atrium.
Anticoagulation and Atrial Fibrillation
During AF (and to some extent, atrial flutter), the atria have incom- plete and ineffective contractions. Blood stasis occurs and may result in the formation of intracardiac thrombus, which may lead to throm- boembolism and stroke. The overall risk of stroke in patients with AF is 5% per year. Certain risk factors may adjust this risk, includ- ing age, gender, rheumatic heart disease, prior stroke, left ventricular dysfunction, vascular disease, hypertrophic cardiomyopathy, left atrial enlargement, hypertension, and diabetes.
Scoring systems have been developed to estimate a patient’s AF-related stroke risk based on his or her constellation of risk factors.
Formerly, the most used system was the CHADS2 score (cardiac failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke). This system has been well validated in assessing the stroke risk of patients with AF. It assigns a single point for age of 75 years or older, diabetes, history of heart failure, and hypertension. It assigns two points for a history of stroke or transient ischemic attack. A score of 0 correlates with a relatively low risk of stroke at 1.9% per year, a score of 1 has a stroke risk of 2.8% per year, a score of 2 has a risk of 4.0% per year, and a score of 3 or higher has a stroke risk of more than 5.9% per year.
The CHADS2 underwent further refinement to increase the gran- ularity of stroke risk stratification with the creation of the CHA2DS2- VASc (vascular disease, age, and sex) scoring system, currently the primary score for thromboembolic risk stratification. In this system, congestive heart failure, hypertension, diabetes mellitus, vascular dis- ease, age between 65 and 74 years, and female gender are assigned 1 point, and age of 75 years or older and prior stroke are assigned 2 points. A CHA2DS2-VASc score of 0 was associated with a 0% stroke rate, a score of 1 with a 0.6% per year risk, a score of 2 with a 1.6% risk, and a score of 3 with a risk of 3.9%. This system may be most useful for identifying truly low-risk patients.
After a patient’s individualized stroke risk is determined, it can be balanced against the risk of anticoagulation to determine what would be appropriate for stroke prevention. A useful tool for estimating bleeding risk due to oral anticoagulation is the HAS-BLED (hyperten- sion, abnormal renal/liver function, stroke, bleeding history or predis- position, labile international normalized ratio, elderly, drugs/alcohol) score. Patients with a HAS-BLED score of 0 had a risk of 0.59 severe bleeds per 100 patient-years, those with a score of 1 had a risk of 1.51, those with a score of 2 had a risk of 3.20, and those with a score of 3 had a risk of 19.51.
In patients with an acceptable bleeding risk, and with a CHA2DS2- VASc score of 2 or greater in men or 3 or greater in women, the 2019 AHA guidelines recommend oral anticoagulation to help prevent embolic stroke. Recommended agents include warfarin, dabigatran, rivaroxaban, apixaban or edoxaban. For patients with low CHA2DS2- VASc scores, aspirin is no longer recommended. Oral anticoagulants might be reasonable for intermediate CHA2DS2-VASc scores (1 in men and 2 for women), but this has less evidence.
Warfarin is the longest-studied antithrombotic used for reducing the rate of AF-related stroke and reduces the risk by 50%. Warfarin can be difficult to administer; the level of blood-thinning effect must be constantly monitored with international normalized ratio (INR) blood testing. An INR less than 2.0 is associated with higher rates of ischemic
stroke; a level greater than 3.0 is associated with increased intracranial bleeding. On average, a therapeutic INR (between 2.0 and 3.0) is main- tained in only two thirds of cases, and there are many drug and dietary interactions with warfarin.
Several newer oral anticoagulants (NOACs) have effectiveness and bleeding risk rates similar to warfarin, but they do not require drug level monitoring. They include dabigatran, rivaroxaban, apixaban, and edoxaban. These drugs have been studied in large patient groups and found to be noninferior to warfarin, and some may be superior in certain aspects. NOACs are preferred in eligible patients over warfarin except in cases of moderate-to-severe mitral stenosis or the presence of a mechanical heart valve.
Percutaneous occlusion of the left atrial appendage with the Watchman device has been compared to Coumadin in patients with nonvalvular atrial fibrillation and found generally to offer similar pro- tection against stroke. Oral anticoagulation remains the preferred ther- apy for stroke prevention in most patients; however, in those who are poor candidates for long-term anticoagulation (because of the propen- sity for bleeding or poor drug tolerance or adherence), the Watchman device provides an alternative.
The highest risk of stroke related to AF occurs at time of conversion to sinus rhythm achieved spontaneously or by chemical or electrical cardioversion. If thrombus has formed within the left atrium or left atrial appendage, it may not leave the atria during AF due to ineffec- tive atrial mechanics. However, after sinus rhythm is restored, the improved atrial function may eject the thrombus and cause embolic stroke or other systemic embolic sequelae. Even with restoration of electrical atrial systole, the recovery of normal atrial mechanics may be delayed several days to weeks (i.e., atrial stunning). To reduce the risk of pericardioversion stroke, it is important to reduce the risk of preexisting thrombus and to prevent formation in the time period immediately after cardioversion.
The risk of preexisting thrombus can be reduced by 3 weeks of oral anticoagulation or Doppler transesophageal echocardiography (TEE) before cardioversion. These steps are recommended for any patient who has been in AF for an unknown period or has been documented to be in AF more than 48 hours. Although thrombi have been identi- fied in patients with AF for shorter periods, current clinical practice presumes that most thrombus formation requires at least 48 hours.
Thrombus related to AF occurs most commonly in the left atrial appendage, which cannot be well visualized by transthoracic echocar- diography; TEE is often recommended before cardioversion for opti- mal imaging of the left atrial appendage. After cardioversion, at least 4 weeks of oral anticoagulation is recommended for everyone, with the exception of low CHA2DS2-VASc score patients (0 in men or 1 in women) who had AF less than 48 hours prior to the cardioversion, in whom postconversion anticoagulation may be omitted.
Acute Management of Atrial Fibrillation: Rate Control
The acute management of AF centers on the control of the ventricu- lar response, timely restoration of sinus rhythm, and identification of potentially reversible factors that might have precipitated the arrhyth- mia. AF with rapid ventricular response results in acute deterioration in stroke volume and cardiac output and an increase in myocardial oxygen demand with the potential for coronary ischemia. Patients who are symptomatic must be controlled promptly. When pursuing rate control for acute AF of recent onset, the fastest way to achieve rate control is the restoration of sinus rhythm. If rate control in ongoing rapidly conducted AF proves difficult or is not well tolerated, cardio- version should be undertaken early.
For the acute control of rapidly conducted AF, intravenous admin- istration of a β-blocker (i.e., esmolol, metoprolol, or propranolol)
or a nondihydropyridine calcium-channel blocker (i.e., diltiazem or verapamil) is preferred. In the setting of decompensated heart failure, the use of a calcium-channel blocker may exacerbate heart failure and should be avoided. In this setting, digoxin is a useful agent for resting rate control. Digoxin is also a useful second-line drug in addition to a calcium-channel or β-blocker for resting rate control. If this therapy is ineffective or not tolerated, intravenous amiodarone is a useful rate control agent, especially in the setting of congestive heart failure, and it may facilitate restoration of sinus rhythm.
Long-term targets for rate control of permanent AF have been a matter of debate. The Rate Control Efficacy in Permanent Atrial Fibrillation II (RACE II) study showed no advantage to strict rate con- trol. Targeting a resting rate of less than 80 beats per minute showed no advantage over a target of less than 110 and was much harder to achieve. For long-term management, the results suggest that achieving a resting heart rate of less than 110 beats per minute may be sufficient and safe.
Acute Management of Atrial Fibrillation: Restoration of Sinus Rhythm
When sinus rhythm is restored in the first 48 hours of acute AF, the thromboembolic risk is low, and anticoagulation is not required.
New-onset AF should be managed with a plan to restore sinus rhythm during this period if possible. At least one half of new-onset AF epi- sodes terminate spontaneously in the first 24 to 48 hours.
Pharmacologic conversion of atrial fibrillation. Pharmacologic conversion of AF can be undertaken when restoration of sinus rhythm is not urgent. Several antiarrhythmic drugs have been effective in increasing the rate of early conversion of AF. Pharmacologic conversion usually is more successful with AF of recent onset than with chronic AF.
Oral agents with efficacy in the early conversion of AF include flecainide, propafenone, and dofetilide. Oral amiodarone and sotalol have been associated with a 27% and 24% conversion rate, respectively, occurring after 28 days of therapy. However, due to low early con- version rates, these oral drugs are not recommended for conversion.
Intravenous agents with efficacy for early conversion include ibutilide and amiodarone. Ibutilide is limited by a relatively high 4% rate of drug-induced QT prolongation and TdP VT. This risk is even higher in the setting of LV dysfunction, electrolyte disturbances, or heart failure.
Ibutilide should be reserved for the pharmacologic conversion of stable patients with a baseline normal QT interval. In contrast, intravenous amiodarone is well tolerated by unstable patients and is the preferred pharmacologic agent for conversion in the critically ill.
Electrical cardioversion of atrial fibrillation. Electrical cardio- version should be performed urgently in the case of severe compromise related to acute AF, including angina, heart failure, hypotension, and shock. Cardioversion should also be attempted at least once electively in most cases of new-onset AF regardless of tolerance. When performing electrical cardioversion, an anterior-posterior patch or paddle position is more effective than the conventional anterior-to-lateral patch or paddle position used for ventricular defibrillation. Although low-output dis- charges may be effective in some patients, a strategy of starting at higher outputs decreases the number of shocks required and the average cumu- lative energy delivered. An initial shock energy of 200 J is recommended.
After a failed initial shock, full output should be used for the next attempt.
Long-Term Maintenance of Sinus Rhythm
Antiarrhythmic therapy. Despite the association of AF with an increase in stroke-related and all-cause mortality, no study has established a benefit for pharmacologic maintenance of sinus rhythm in terms of stroke risk or survival. This may be because AF is
115 CHAPTER 9 Cardiac Arrhythmias
merely a marker and not a mechanism of mortality. It may also be a consequence of the relative inefficacy of pharmacologic therapy in the maintenance of sinus rhythm and the difficulty of establishing whether patients thought to be in sinus rhythm are consistently in sinus rhythm at follow-up.
The largest and best designed trial addressing this issue was the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial. The study included 4060 patients randomly assigned to rhythm control with antiarrhythmic drugs, most commonly amiodarone, or to rate control without attempts to maintain sinus rhythm. AFFIRM demonstrated no advantage in stroke or mortality rates using a strategy of sinus rhythm maintenance compared with rate control. Either strategy can be offered to patients with an expectation of similar outcomes with regard to hard end points. The decision to pursue sinus rhythm usually is determined by the management of symptoms that may be better addressed by maintaining sinus rhythm in selected patients.
In the absence of antiarrhythmic drugs, more than 80% of patients relapse during the first year after cardioversion of AF. Antiarrhythmic drugs remain the primary strategy for maintaining sinus rhythm after cardioversion and for preventing symptomatic episodes in patients with paroxysmal AF. However, antiarrhythmic therapy has many lim- itations, and alternative ablative therapies may over time overtake anti- arrhythmic therapy in the management of AF.
All antiarrhythmic drugs have the potential for proarrhythmia, the unintended precipitation of a new arrhythmic problem caused by the drug. Adverse rhythm effects of drugs may include sinus node dysfunc- tion, heart block, promotion of drug-slowed atrial flutter permitting rapid 1:1 conduction, and promotion of potentially lethal ventricular arrhythmias. Class I drugs such as flecainide, propafenone, and diso- pyramide may result in significant direct myocardial depression and consequent exacerbation of heart failure. The array of potential adverse effects of antiarrhythmic drugs is beyond the scope of this chapter, but certain essential concepts are important to recognize.
Class I drugs such as flecainide and propafenone, which work by slowing conduction, have a high risk of ventricular proarrhythmia and potential for sudden death in the setting of heart failure, LV dysfunc- tion, and coronary artery disease. Use of these drugs is restricted to patients with preserved cardiac function and no evidence of obstruc- tive coronary artery disease. However, in this selected group of patients with normal hearts, these drugs are exceedingly safe, well tolerated, and often effective.
Class III drugs, which prolong repolarization and refractoriness, include sotalol, dofetilide, dronedarone, and amiodarone. They are safe for patients with coronary artery disease, and in the case of dofeti- lide and amiodarone, they are safe for those with congestive heart fail- ure. However, sotalol and dofetilide may provoke TdP, even in patients with normal cardiac function, and they must be used with caution.
Amiodarone has greater long-term efficacy than other drugs and a lower risk of proarrhythmia, but long-term somatic toxicity consist- ing of thyroid dysfunction, pulmonary, and occasional hepatotoxic- ity limits the use of this drug in older patients or those with limited expected longevity or an inability to safely tolerate alternative agents due to advanced cardiac disease or proarrhythmia. Amiodarone is highly effective for the short-term, acute management of arrhythmias in critically ill patients when the potential risk of long-term toxicity is not an issue.
Dronedarone was derived by modification of the amiodarone mol- ecule. Like amiodarone, the drug has a low risk of proarrhythmia and TdP VT. Unlike amiodarone, the drug does not cause thyroid toxic- ity. In common use, hepatotoxicity is also uncommon with drone- darone. However, rare cases of hepatic failure have been associated
with dronedarone use. Dronedarone has increased mortality rates for patients with recently decompensated heart failure and when used as a simple rate control agent in patients with permanent AF. It is contra- indicated in these settings.
In addition to being useful agents for the prevention of AF, sotalol, dronedarone, and amiodarone provide substantial rate control during relapses of AF. However, rate control with other antiarrhythmic agents may not be adequate to prevent rapid conduction with relapse, and class I drugs such as flecainide may accelerate response at the time of relapse. Antiarrhythmic drugs other than sotalol, dronedarone, or amiodarone should therefore be combined with a rate control agent such as a β-blocker or nondihydropyridine calcium-channel blocker during long-term therapy. Fig. 9.7 is a proposed strategy for anti- arrhythmic drug selection for the long-term maintenance of sinus rhythm in patients with AF.
Surgical ablation of atrial fibrillation. The surgical treatment of AF was pioneered by Cox with the development of the atrial maze procedure. The procedure was predicated on the concept that AF was maintained by multiple interacting wave fronts of activity. By surgically dividing the atria into narrow channels, most with connection back to the sinus node, it was thought that AF could be abolished while preserving physiologic activation and contraction of the atrium. The circuitous path left for atrial activation and the multiple barriers created in the atrium intended to prevent AF gave rise to the term maze procedure to describe the technique. The initial procedure was thought to be highly successful but was associated with significant surgical risks and problems with sinus node dysfunction. Because of the surgical complexity of making and then closing multiple incisions in the atria and the complications associated with the procedure, the initial cut- and-sew maze procedure has fallen out of clinical use.
No (or minimal)
Flecainide Propafenone
Sotalol
Amiodarone Dofetilide
Yes
No Yes
Heart disease
LVH ≥1.4 cm CAD
Sotalol Dofetilide
Amiodarone Amiodarone
Dofetilide
Hypertension Heart failure
Catheter ablation Catheter
ablation
Amiodarone
Catheter ablation
Flecainide Propafenone
Sotalol
Fig. 9.7 A strategy for the selection of therapy to maintain sinus rhythm in patients with recurrent atrial fibrillation. Patients are stratified by the presence or absence of structural heart disease, and drugs expected to have the greatest efficacy and lowest therapeutic risk in each group are selected. Catheter ablation becomes a therapeutic option after failure of at least one antiarrhythmic drug. The class IC drugs flecainide and propafenone are not advised for patients with heart failure or coronary artery disease (CAD). Amiodarone is an acceptable first-line drug for those with heart failure and severe left ventricular hypertrophy. Because of its potential for somatic toxicity, amiodarone is otherwise reserved as a second-line agent that is used as an alternative to catheter ablation.