Release Date: February 1, 2010
Expiration Date: February 29, 2012
FACULTY:
Evangelina Berrios-Colon, PharmD, BCPS, CACP
The Brooklyn Hospital Center
Clinical Assistant Professor of Pharmacy Practice,
Long Island University,
Agnes Cha, PharmD
PGY-2 Ambulatory Care Resident,
The Brooklyn Hospital Center,
Atrial fibrillation (AF) is the most common cardiac arrhythmia, with a prevalence of 0.4% to 1.0% in the general population.1 Prevalence increases with age, reaching 8% in patients older than 80 years. The average age of patients with AF is 75 years, and the incidence of the condition is relatively equal between men and women. AF is responsible for about one-third of hospital admissions for cardiac-rhythm disturbances. Hospitalizations due to AF have increased by 66% in the past 20 years, owing mostly to more frequent diagnosis resulting from the use of ambulatory monitoring devices, the aging of the population, and the increased prevalence of heart disease.2 Since AF is frequently encountered by pharmacists and other health care providers in the ambulatory setting, this article aims to review the basic pathophysiology of AF and various treatment options for the best management of patients with this condition.
Pathophysiology
A normal heartbeat is initiated by the body’s natural pacemaker, the sinoatrial node in the right atrium, which spreads electrical activity across the right and left atria, resulting in a contraction (FIGURE 1). This contraction drives blood into and fills the chambers of the ventricles, which are responsible for pumping blood throughout the body. The electrical signal is slightly delayed by the atrioventricular (AV) node and then spreads rapidly through the bundle of His to the Purkinje fibers, resulting in a ventricular contraction. This normal conduction is termed sinus rhythm. Most of the general population has a resting heart rate (HR) of 60 to 80 beats per minute (bpm).3AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial electrical conduction, which results in a deterioration of mechanical function.4 In AF, disorganized atrial electrical conduction results in rapid atrial bpm (400-600).5 This activity results in the loss of an atrial contraction—or atrial kick—sufficient to promote cardiac output. The AV node allows only 1 or 2 out of every 3 atrial beats to pass through to the ventricles, but the resting HR is still 110 bpm to 180 bpm.3 The HR, or pulse, in AF is “irregularly irregular” because of the variable supraventricular impulses that penetrate the AV node.
Although the pathophysiologic mechanisms are not completely understood, it is generally accepted that AF is a result of either multiple reentrant wavelets or a focal triggering mechanism involving automaticity.4 These mechanisms may coexist, as they are not mutually exclusive. The multiple-wavelet hypothesis involves multiple atrial reentrant loops, or wavelets, that occur simultaneously in the left and right atria and cause self-perpetuating “daughter wavelets.”4,5 The perpetuation of wavelets is favored by increased atrial mass, shortened refractory periods, and delayed conduction, collectively promoting sustained AF. The longer the heart is in AF, the less likely it is that the restoration and maintenance of sinus rhythm will be successful, following the notion that “AF begets AF.”4,5
The second mechanism is triggered by a focal source, and it has been established that the pulmonary veins are a major source of triggers that can initiate AF.6 Myocardial muscle fibers extend from the left atrium into the pulmonary veins (1-3 cm), and these muscular sleeves are the source of focal firing. Thus, if AF is caused by this focal source, ablation of that focal trigger may terminate AF (discussion follows). However, in longstanding persistent AF, atrial remodeling occurs, which may enhance the number of triggers and shift them to other locations.
Untreated AF may cause complications, including an increased risk of cerebral thromboembolism, development of heart failure (HF), increased mortality, increased left atrial pressure and volume, shortened diastolic ventricular filling period, AV valvular regurgitation, and irregular and rapid ventricular rate.6 In addition, as mentioned earlier, persistent AF can result in electrical and anatomical remodeling of the left atrium, which may enhance the sustainment of AF.
Classification
There are different classifications of AF. The American College of Cardiology/American Heart Association and the European Society of Cardiology (ACC/AHA/ESC) in 2001 established a classification system (revised in 2006) that is widely used.4Paroxysmal AF is defined as recurrent AF (≥2 episodes) that terminates spontaneously within 7 days. Persistent AF is sustained beyond 7 days, or lasts less than 7 days but requires pharmacologic or electrical cardioversion. Long-standing persistent AF is when a patient presents with continuous AF for more than 1 year. Permanent AF is classified as AF in which cardioversion either has failed or has not been attempted because the patient has decided not to pursue restoration of sinus rhythm by any means.5
Risk Factors
Various factors predispose patients to AF.4 Reversible causes of AF may include alcohol intake (“holiday heart syndrome”), surgery, electrocution, myocardial infarction (MI), myocarditis, pulmonary embolism, and hyperthyroidism. Successful treatment of the underlying condition usually eliminates the AF. Obesity is associated with AF because as body-mass index increases, so does the size of the left atrium, resulting in atrial dilation. Other disease states associated with AF are primarily cardiac conditions: mitral valve disease, HF, coronary artery disease (CAD), hypertension (HTN), left ventricular hypertrophy, and cardiomyopathy.4,5However, 30% to 45% of paroxysmal AF cases and 20% to 25% of persistent AF cases occur in young patients without an underlying medical condition, a state known as lone AF.4 Lone AF may be a familial arrhythmia, or a causal underlying condition may appear over time.
Diagnosis
Diagnosis of AF requires electrocardiogram (ECG) documentation by at least a single-lead recording during the arrhythmia. Suspected arrhythmias also may be documented by Holter monitor, a small ambulatory ECG device that records 24 hours of continuous electrocardiographic signals. The ECG will display rapid oscillations of varying amplitude, shape, and timing that replace consistent P waves (FIGURE 2).4 The resulting ventricular response is an irregularly irregular contraction.
Signs and Symptoms
Classic symptoms of AF are palpitations, chest pain, dyspnea, fatigue, lightheadedness, and syncope—or there may be no symptoms at all. AF may initially present as an embolic complication or exacerbation of HF. Polyuria also may occur as episodes of AF begin or terminate because of the release of atrial natriuretic peptide.Physical examination may reveal irregular pulse, irregular jugular venous pulsations, variations in intensity of the first heart sound, or absence of the fourth heart sound.4 AF may manifest clinically as palpitations, significant hemodynamic or thromboembolic consequences, or an asymptomatic period of unknown duration. Hemodynamic complications involve irregular ventricular response, rapid HR, impaired coronary blood flow, decreased cardiac output, and tachycardia-induced cardiomyopathy.
Management
The ultimate treatment goals for AF are the restoration and maintenance of sinus rhythm and the prevention of thromboembolic complications.4 Controlling the ventricular rate in AF without actively attempting to restore sinus rhythm with pharmacologic agents is a safe alternative. In many patients, symptom relief can be obtained by controlling HR. Once adequate rate control is obtained, many patients are unaware of episodes of paroxysmal AF.Cardioversion
Patients with persistent AF may undergo elective cardioversion to restore sinus rhythm. Typically, cardioversion is not recommended for patients with paroxysmal AF; however, it may be necessary if the AF is responsible for acute HF, hypotension, or worsening angina in a CAD patient. Cardioversion may be performed either pharmacologically or electrically, as direct-current cardioversion (DCC). Both methods are effective; however, there are clear disadvantages that must be considered.Pharmacologic cardioversion carries the risk of drug-induced torsades de pointes or other serious arrhythmias. More importantly, it is less effective than DCC using biphasic shocks, with respective success rates of 78% for DCC and 59% for pharmacologic cardioversion.4,7 However, electrical cardioversion requires conscious sedation or anesthesia, which may be disadvantageous. There is no evidence that the risk of thromboembolism or stroke differs between the two methods; thus, recommendations for anticoagulation are identical for pharmacologic and electrical cardioversion.4,5
Pharmacologic Cardioversion: Pharmacologic cardioversion may be initiated on an inpatient or outpatient basis, but it is most effective when initiated within 7 days of onset. The advantages of antiarrhythmics over placebo are modest after 24 to 48 hours of new onset of AF.4 In addition, some agents have a delayed onset of action, and cardioversion may not occur for several days.8
Medications with proven efficacy for in-hospital cardioversion of AF of up to 7 days’ duration are the class Ic antiarrhythmics flecainide and propafenone and the class III antiarrhythmics dofetilide, ibutilide, and amiodarone (TABLE 1).4,5 Quinidine, disopyramide, or procainamide (class Ia antiarrhythmics) may be considered; however, the value of these agents is not well established. In AF that has been present for more than 7 days, the class III antiarrhythmics have proven efficacy. Digoxin and sotalol may be harmful if used for cardioversion and therefore are not recommended.4
Amiodarone may be initiated safely on an outpatient basis, as it has low proarrhythmic potential and causes minimal depression of myocardial function (although a loading dose may be necessary on an inpatient basis for faster restoration in a hemodynamically compromised patient). Amiodarone, with its active metabolite desethylamiodarone, blocks sodium, potassium, and calcium channels. Amiodarone is approved for the treatment of lethal ventricular arrhythmias, but not for the management of AF; nonetheless, it is widely prescribed for the latter condition.9
It is recommended that all antiarrhythmics be started at a low dose and titrated up based on patient response. An ECG should be monitored after every dosage change. Specific recommendations state that quinidine, procainamide, disopyramide, and dofetilide should be initiated only on an inpatient basis.4
Electrical Cardioversion: DCC consists of delivery of an electrical shock that is synchronized with the R wave of the QRS complex to ensure that electrical stimulation does not occur during the repolarization phase of the cardiac cycle. Patients undergoing DCC should be in a fasting state and under general anesthesia. If a monophasic waveform defibrillator is used, 200 J or 360 J of energy is recommended.10 Biphasic defibrillators require less energy to convert arrhythmia into sinus rhythm, so it is recommended to start with 200 J.11
Immediate DCC is recommended for patients in AF who are experiencing hemodynamic instability or rapid tachycardia. DCC also is advised in the absence of hemodynamic instability if the symptoms are unacceptable to the patient. Cardioversion has a high rate of efficacy for restoring sinus rhythm; however, recurrent AF is common. If the cardioversion is unsuccessful, additional DCC beyond a second attempt has limited benefit and should be used only in selected symptomatic patients. However, infrequently repeated cardioversions are acceptable for patients who become highly symptomatic during relapses of AF.4 Patient preference regarding the use of DCC to help manage their recurrent AF should be considered.
Data have suggested that initiation of antiarrhythmics before DCC can augment immediate success and prevent early recurrence.4 Pretreatment with amiodarone, flecainide, ibutilide, propafenone, or sotalol may be used as pharmacologic enhancement while in the hospital. Outpatient initiation of antiarrhythmics may be considered only in patients without heart disease.
Maintenance of Sinus Rhythm
When AF is a chronic disorder, patients most likely will need long-term antiarrhythmic treatment to maintain sinus rhythm, suppress symptoms, and improve exercise tolerance. Most AF patients eventually experience recurrence, except for those with postoperative AF or self-limited AF secondary to transient or acute illness. See TABLE 2 for predisposing factors to recurrent AF.12FIGURE 3). Selection of the appropriate drug is based first on safety and then tailored to any underlying heart disease. Flecainide, propafenone, and sotalol have been shown to be efficacious for lone AF; beta-blockers also may be an option. Amiodarone and dofetilide are other viable alternatives.4
Most clinicians focus initially on maintenance of sinus rhythm and typically choose a rate-control strategy when rhythm control fails. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) was a clinical trial that randomized 4,060 patients at risk for stroke to either rhythm control or rate control and found no between-group difference in mortality.13 The researchers concluded that rhythm control offers no survival advantage over rate control and that rate control has potential advantages, such as lower risk of adverse drug effects. A trend toward an increase in AF recurrence and thromboembolic events was noted in the rhythm-control cohort. The ACC/AHA/ESC 2006 guidelines state that rate control is a reasonable option in asymptomatic AF patients.4
The Pharmacologic Intervention in Atrial Fibrillation (PIAF) trial studied patients in AF of 7 to 360 days’ duration.14 Patients were randomized to receive either rhythm control with amiodarone or rate control with diltiazem. Both groups were anticoagulated with warfarin to a target international normalized ratio (INR) of 2.0 to 3.0. After 1 year of follow-up, there was no difference between the groups in symptoms related to AF—specifically, palpitations, dyspnea, and dizziness, as well as quality of life assessed by detailed interviews.
A rate of 60 to 80 bpm while the patient is at rest and a rate of 90 to 100 bpm during exercise are the target goals for adequate rate control.4 In most patients, nondihydropyridine calcium channel blockers and beta-blockers (with or without digoxin) are the drugs of choice for rate control. Long-term rhythm control with amiodarone, dronedarone, sotalol, or propafenone may be another option for maintaining sinus rhythm.
Historically, digoxin has been used to restore normal sinus rhythm; however, over the past 10 years it has fallen out of favor because of its slow onset (usually >24-48 hours to obtain HR <100 bpm) and extensive toxicities.15 Currently, it is used mostly for rate control in patients with HF.
Selection of a rate-control strategy should be based on patient-specific factors like comorbidities and contraindications (TABLE 3).
Anticoagulation
Prevention of Thromboembolism After Cardioversion: In patients who require cardioversion for restoration of normal sinus rhythm and have been in AF for more than 48 hours, anticoagulation is needed in order to prevent clot growth, keep new clots from forming, and allow existing clots to become organized and adhere to the atrial wall. Patients with AF are at risk for cardioembolic stroke, mainly owing to formation of a thrombus due to stasis in the left atrial appendage (LAA). For detecting thrombus formation, transesophageal echocardiography (TEE) is more sensitive and specific than transthoracic echocardiography.A successful cardioversion may stun the LAA and result in increased risk of a thromboembolic event. The risk is the same regardless of type of cardioversion—pharmacologic, electrical, or spontaneous. More than 80% of thromboembolic events occur during the first 3 days after cardioversion. Atrial stunning is at its highest immediately after cardioversion;however, improvement of atrial transport of blood flow may take up to a few weeks. This underscores the importance of anticoagulation in patients undergoing cardioversion.17
Patients with AF of more than 48 hours’ duration or ofunknownduration should be anticoagulated with warfarin (target INR 2.0-3.0) for at least 3 weeks prior to cardioversion.17 Even after cardioversion has restored sinus rhythm, anticoagulation should be continued for at least another 4 weeks. If a patient needs immediate cardioversion owing to hemodynamic instability such as angina, MI, shock, or pulmonary edema, low-molecular-weight heparin (LMWH) or IV heparin should be administered (unless contraindicated) by initial IV bolus at 80 U/kg, then continuous infusion at 18 U/kg/h to a goal-activated partial thromboplastin time of 50 to 70 sec.17 Anticoagulation with warfarin is recommended for at least 4 weeks thereafter.
The American College of Chest Physicians (ACCP) 2008 guidelines on antithrombotic therapy in AF recommend that, in patients who have had AF for less than 48 hours, cardioversion may be performed immediately without prior anticoagulation because it is unlikely that the atrium has had enough time to form a thrombus.17 However, in consideration of atrial stunning—a consequence of electrical cardioversion that is associated with thrombus formation and embolic stroke—anticoagulation may be continued for an additional 4 weeks.18
As an alternative to an anticoagulation period before cardioversion, TEE may be performed to rule out a thrombus in the left atrium or LAA. If no thrombus is identified, cardioversion is reasonable, likely with a period of anticoagulation for 4 weeks afterward. In practice, TEE may be performed before cardioversion, even with prior anticoagulation. If a thrombus is found, the patient will have a longer period of anticoagulation.17 TEE should be repeated to confirm resolution of the clot.
The use of LMWH instead of unfractionated heparin (UFH) in AF patients is based mostly on extrapolation from data concerning venous thromboembolic disease states.19 Some advantages of LMWH over UFH are longer half-life, predictable clearance, and antithrombotic response. Patients receiving LMWH may self-administer the medication subcutaneously on an outpatient basis.
Long-Term Prevention of Thromboembolism: To prevent stroke in at-risk patients, the ACCP guidelines recommend anticoagulation with warfarin to an INR of 2.0 to 3.0 (target 2.5).17 At-risk patients are defined as those with prosthetic heart valves, rheumatic valvular disease, history of thromboembolism, HTN, left ventricular dysfunction, or age greater than 75 years.
In all patients who may be placed on oral anticoagulation, a risk evaluation (CHADS2) must be performed to determine stroke risk. The CHADS2 score is based on a point system that assigns values to various risk factors (CHF, HTN, age >75 years, diabetes, prior stroke or transient ischemic attack) that predispose patients to thromboembolism.20 A CHADS2 score of 0 warrants treatment with aspirin, not warfarin; however, if the CHADS2 score is greater than 1, long-term anticoagulation with warfarin (target INR 2.0-3.0) is warranted to reduce stroke risk. This predictive model was based on data from 1,733 Medicare beneficiaries aged 65 to 95 years with nonvalvular heart disease who were not given warfarin. Higher values were associated with stroke; however, very few patients had a score of 0 or greater than 5. The CHADS2 score and stroke risk are defined in TABLES 4 and 5.
| Table 4. Definition of CHADS2 Score | |
| Risk Criterion | Score |
| Cardiac failure Hypertension Age >75 y Diabetes Prior Stroke or TIA | 1 1 1 1 2 |
TIA: transient ischemic attack. Source: Reference 20. | |
| Table 5. Stroke Risk According to CHADS2 Score | |
| Score | Adjusted Risk (%/y) |
| 0 1 2 3 4 5 6 | 1.9 2.8 4.0 5.9 8.5 12.5 18.2 |
Source: Reference 20. | |
The addition of clopidogrel to aspirin therapy to prevent major vascular events in patients with AF was evaluated in 7,554 patients who were not receiving warfarin.22 It was found that the inclusion of clopidogrel reduced the risk of major vascular events (specifically stroke), but increased the risk of major hemorrhage.
Interruption of anticoagulation may be necessary for surgery or invasive diagnostic procedures. Anticoagulation with warfarin may be interrupted up to 5 days prior to a procedure, and “bridge therapy” with LMWH or IV heparin may be initiated. The ACC/AHA/ESC 2006 guidelines state that, in patients with nonvalvular AF who are interrupting oral anticoagulation, it is appropriate not to overlap with LMWH or IV heparin if anticoagulation is being interrupted for only up to 1 week. However, the ACCP guidelines state that it is appropriate not to overlap with LMWH or IV heparin if anticoagulation is being interrupted for up to 2 weeks.17 In patients at high risk for stroke, bridge therapy is warranted.
Individualized Pharmacotherapeutic Plan
Pharmacists have numerous opportunities to optimize pharmacotherapy for patients with a history of AF. Ensuring that patients with specific risk factors for cardioembolic stroke are receiving treatment with either an oral anticoagulant or aspirin is vital. Educating patients on their target intensity of anticoagulation, potential drug interactions, dietary restrictions, and self-monitoring of signs and symptoms of bleeding will help prevent adverse sequelae. At every patient encounter, the medication regimen should be reviewed and intervention take place if drug interactions are present. Additionally, patients taking anticoagulants must be assessed regularly for signs and symptoms of bleeding.Other Treatment Options
Pulmonary Vein Antrum Isolation (PVAI): If a patient continues to have AF that is refractory to antiarrhythmics, PVAI (also known as pulmonary vein ablation) may be considered. PVAI differs from AV nodal ablation, which is used in conjunction with permanent pacemaker implantation to control HR. Over the past decade, catheter ablation of AF has evolved from an experimental method to a commonly performed procedure.6Ablation procedures prevent AF by eliminating the triggering source. They accomplish this by creating circumferential lesions around the pulmonary vein ostium to electrically isolate the focal source of pulmonary veins. PVAI also may alter the tissue located near the atrial–pulmonary vein junction, eliminating the substrate for reentrant circuits that may perpetuate AF. The procedure uses radiofrequency energy delivered by transvenous electrode catheter. The goal of PVAI is to improve a patient’s quality of life, so it is indicated for symptomatic AF that is refractory or intolerant to at least one antiarrhythmic.
Recent randomized clinical trials have demonstrated freedom from recurrent AF in the range of 56% to 86% of patients, and all studies to date have shown improved quality of life.5 Similar to cardioversion, restoring sinus rhythm by ablation puts the patient at risk for thromboembolism. In addition, the procedure leaves areas of damaged left atrial endothelium where a thrombus could develop. For these reasons, warfarin is recommended for at least 2 months after AF ablation, with a target INR of 2.0 to 3.0.6 Other complications of AF ablation include cardiac tamponade, pulmonary vein stenosis, esophageal injury, atrio-esophageal fistula, phrenic nerve injury, vascular complications, and radiation exposure.6
Dronedarone: The FDA approved dronedarone (Multaq) for the treatment of AF and atrial flutter in July 2009, making it the first medication for AF treatment to be approved in 25 years. Dronedarone is a noniodinated derivative of amiodarone without many of the toxicities that are common with amiodarone. Dronedarone’s mechanism of action is similar to that of amiodarone. Dronedarone exerts its action by blocking potassium, sodium, and calcium channels and exhibits antiadrenergic properties. The usual dose of dronedarone for paroxysmal or persistent AF is 400 mg by mouth twice daily with morning and evening meals. Dronedarone has been associated with a 24% reduction in hospitalizations and deaths due to AF and other cardiovascular complications versus placebo.23 However, higher death rates have occurred in patients with a history of severe HF receiving dronedarone, which resulted in the drug receiving a black box warning. Common side effects of dronedarone include diarrhea, nausea, vomiting, fatigue, and weakness.24
