The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57:M352-M363 (2002)
© 2002 The Gerontological Society of America
Management of the Older Person With Atrial Fibrillation
Wilbert S. Aronowa
a Department of Medicine, Divisions of Cardiology and Geriatrics, Westchester Medical Center/ New York Medical College, Valhalla
Wilbert S. Aronow, Cardiology Division, New York Medical College, 23 Pebble Way, New Rochelle, NY 10804 E-mail: WSAronow{at}aol.com.
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Abstract
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Atrial fibrillation (AF) is associated with a higher incidence of mortality, stroke, and coronary events than is sinus rhythm. AF with a rapid ventricular rate may cause a tachycardia-related cardiomyopathy. Immediate direct-current (DC) cardioversion should be performed in patients with AF and acute myocardial infarction, chest pain due to myocardial ischemia, hypotension, severe heart failure, or syncope. Intravenous beta blockers, verapamil, or diltiazem may be given to slow immediately a very rapid ventricular rate in AF. An oral beta blocker, verapamil, or diltiazem should be used in persons with AF if a fast ventricular rate occurs at rest or during exercise despite digoxin. Amiodarone may be used in selected patients with symptomatic life-threatening AF refractory to other drugs. Nondrug therapies should be performed in patients with symptomatic AF in whom a rapid ventricular rate cannot be slowed by drugs. Paroxysmal AF associated with the tachycardia-bradycardia syndrome should be treated with a permanent pacemaker in combination with drugs. A permanent pacemaker should be implanted in patients with AF and with symptoms such as dizziness or syncope associated with ventricular pauses greater than 3 seconds that are not drug-induced. Elective DC cardioversion has a higher success rate and a lower incidence of cardiac adverse effects than does medical cardioversion in converting AF to sinus rhythm. Unless transesophageal echocardiography has shown no thrombus in the left atrial appendage before cardioversion, oral warfarin should be given for 3 weeks before elective DC or drug cardioversion of AF and should be continued for at least 4 weeks after maintenance of sinus rhythm. Many cardiologists prefer, especially in older persons, ventricular rate control plus warfarin rather than maintaining sinus rhythm with antiarrhythmic drugs. Digoxin should not be used to treat patients with paroxysmal AF. Patients with chronic or paroxysmal AF at high risk for stroke should be treated with long-term warfarin to achieve an International Normalized Ratio of 2.0 to 3.0. Patients with AF at low risk for stroke or with contraindications to warfarin should receive 325 mg of aspirin daily.
ATRIAL fibrillation (AF) is a cardiac rhythm that has irregular undulations of the baseline electrocardiogram (ECG) of varying amplitude, contour, and spacing known as fibrillation waves, with the atrial rate between 350 and 600 beats per minute. The fibrillation waves are seen best in leads V1, II, III, and aVF. The fibrillation waves may be large and coarse, or they may be fine with an almost flat ECG baseline. The ventricular rate in AF is irregular unless complete atrioventricular (AV) block or dissociation is present. The contour of the QRS complex in AF is normal unless there is prior bundle branch block, an intraventricular conduction defect, or aberrant ventricular conduction.
If AF is associated with a slow regular ventricular response, there is complete AV block with an AV junctional escape rhythm or idioventricular escape rhythm. Myocardial infarction, degenerative changes in the conduction system, and drug toxicity such as digitalis toxicity are major causes of complete AV block. If AF is associated with a regular ventricular response between 60 and 130 beats per minute, there is complete AV dissociation with an accelerated AV junctional rhythm caused by an acute inferior myocardial infarction, digitalis toxicity, open heart surgery, or myocarditis, usually rheumatic. Regularization of the ventricular response in AF may also occur in patients with complete AV dissociation due to ventricular tachycardia or a ventricular paced rhythm.
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Prevalence
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AF is the most common sustained cardiac arrhythmia. The prevalence of AF increases with age (1)(2)(3)(4)(5). In the Framingham Study, the prevalence of chronic AF was 2% in persons aged 60 to 69 years, 5% in persons aged 70 to 79 years, and 9% in persons aged 80 to 89 years (1). In a study of 2101 persons with a mean age of 81 years, the prevalence of chronic AF was 5% in persons aged 60 to 70 years, 13% in persons aged 71 to 90 years, and 22% in persons aged 91 to 103 years (2). Chronic AF was present in 16% of 1160 men with a mean age of 80 years, and in 13% of 2464 women with a mean age of 81 years (3). In 5201 persons aged 65 years and older in the Cardiovascular Health Study, the prevalence of AF was 6% in men and 5% in women (4). In 1563 persons with a mean age of 80 years who were living in the community and seen in a geriatrics practice, the prevalence of chronic AF was 9% (5). In the Cardiovascular Health Study, the incidence of AF was 19.2 per 1000 person-years (6).
AF may be paroxysmal or chronic. Episodes of paroxysmal AF may last from a few seconds to several weeks. Sixty-eight percent of persons presenting with AF of less than 72 hours' duration spontaneously converted to sinus rhythm (7).
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Predisposing Factors
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Multiple, small reentrant circuits arising in the atria, colliding, being extinguished, and arising again usually cause AF (8). Rapidly firing foci usually located in or near the pulmonary veins may also cause AF (9). Factors responsible for onset of AF include triggers that induce the arrhythmia and the substrate that sustains it. Atrial inflammation or fibrosis acts as a substrate for the development of AF. Triggers of AF include acute atrial stretch, accessory AV pathways, premature atrial beats or atrial tachycardia, sympathetic or parasympathetic stimulation, and ectopic foci occurring in sleeves of atrial tissue within the pulmonary veins or vena caval junctions (10). Table 1 shows predisposing factors for AF.
Table 2 shows the higher prevalence of echocardiographic findings in 254 older persons with AF compared to 1445 older persons with sinus rhythm. Mean age of patients was 81 years (11). The Framingham Study demonstrated that low serum thyrotropin levels were independently associated with a 3.1-times increase in the development of new AF in older patients (12).
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Table 2. Prevalence of Echocardiographic Findings in 254 Older Persons With Chronic Atrial Fibrillation Compared to 1445 Older Persons With Sinus Rhythm
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Associated Risks
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The incidence of death from cardiovascular causes was 2.7 times higher in women and 2.0 times higher in men with chronic AF than in women and men with sinus rhythm in the Framingham Study (13). The Framingham Study also found that after adjustment for preexisting cardiovascular conditions, the odds ratio for mortality in persons with AF was 1.9 in women and 1.5 in men (14). At the 42-month follow-up of 1359 persons with heart disease, mean age 81 years, patients with chronic AF had a 2.2-times higher relative risk of having new coronary events than patients with sinus rhythm after controlling for other prognostic variables (15).
AF was present in 22% of 106,780 persons aged 65 years or older with acute myocardial infarction (MI) in the Cooperative Cardiovascular Project (16). Compared with sinus rhythm, patients with AF had a higher in-hospital mortality (25% vs 16%), 30-day mortality (29% vs 19%), and 1-year mortality (48% vs 33%) (16). AF was an independent predictor of in-hospital mortality (odds ratio = 1.2), 30-day mortality (odds ratio = 1.2), and 1-year mortality (odds ratio = 1.3) (16). Older patients developing AF during hospitalization had a worse prognosis than older patients presenting with AF (16). In the Global Use of Strategies to Open Occluded Coronary Arteries study, 906 of 13,858 patients (7%) developed AF during hospitalization (17). After adjusting for baseline differences, AF increased the 30-day mortality (odds ratio = 1.6) and the 1-year mortality (odds ratio = 1.6) (17).
In the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptors Suppression Using Integrilin Therapy trial, AF developed in 6.4% of 9432 patients with acute coronary syndromes without ST-segment elevation (18). After adjustment for other variables, patients with AF had a higher 30-day mortality (hazard ratio = 4.0) and 6-month mortality (hazard ratio = 3.0) than patients without AF (18).
AF is also an independent risk factor for stroke, especially in older persons (1)(2). In the Framingham Study, the relative risk of stroke in patients with nonvalvular AF compared with patients with sinus rhythm was increased 2.6 times in patients aged 60 to 69 years, increased 3.3 times in patients aged 70 to 79 years, and increased 4.5 times in patients aged 80 to 89 years (1). Chronic AF was an independent risk factor for thromboembolic (TE) stroke with a relative risk of 3.3 in 2101 persons with a mean age of 81 years (2). The 3-year incidence of TE stroke was 38% in older persons with chronic AF and 11% in older persons with sinus rhythm (2). The 5-year incidence of TE stroke was 72% in older persons with AF and 24% in older persons with sinus rhythm (2). At 37-month follow-up of 1476 patients who had 24-hour ambulatory ECGs, the incidence of TE stroke was 43% for 201 patients with AF (relative risk = 3.3), 17% for 493 patients with paroxysmal supraventricular tachycardia, and 18% for 782 patients with sinus rhythm (19).
In 2384 persons with a mean age of 81 years, AF was present in 17% of older persons with left ventricular hypertrophy (LVH) and in 8% of persons without LVH (20). Both AF (risk ratio = 3.2) and LVH (risk ratio = 2.8) were independent risk factors for new TE stroke at 44-month follow-up (20). The higher prevalence of LVH in older patients with chronic AF contributes to the increased incidence of TE stroke in older patients with AF.
Both AF (risk ratio = 3.3) and 40% to 100% of extracranial carotid arterial disease (ECAD) (risk ratio = 2.5) were independent risk factors for new TE stroke at 45-month follow-up of 1846 persons with a mean age of 81 years (21). Older persons with both chronic AF and 40% to 100% of ECAD had a 6.9 times higher probability of developing new TE stroke than older persons with sinus rhythm and no significant ECAD (21).
Cerebral infarctions were found in 22% of 54 autopsied patients aged 70 years or older with paroxysmal AF (22). Symptomatic cerebral infarction was 2.4 times more common in older patients with paroxysmal AF than in older patients with sinus rhythm (22). AF also causes silent cerebral infarction (23).
AF predisposes to congestive heart failure (CHF) in older patients. As much as 30% to 40% of left ventricular (LV) end-diastolic volume may be attributable to left atrial contraction in older persons. Absence of a coordinated left atrial contraction decreases late diastolic filling of the LV because of loss of the atrial kick. In addition, a rapid ventricular rate in AF shortens the LV diastolic filling period, further decreasing LV filling.
A retrospective analysis of the Studies of Left Ventricular Dysfunction Prevention and Treatment Trials demonstrated that AF was an independent risk factor for all-cause mortality (relative risk = 1.3), progressive pump failure (relative risk = 1.4), and death or hospitalization for CHF (relative risk = 1.3) (24). AF was present in 37% of 355 patients with a mean age of 80 years, with prior MI, CHF, and abnormal LV ejection fraction (EF) and in 33% of 296 patients with a mean age of 82 years, with prior MI, CHF, and normal LVEF (25). In this study, AF was an independent risk factor for mortality with a risk ratio of 1.5 (25).
A rapid ventricular rate associated with chronic or paroxysmal AF may cause a tachycardia-related cardiomyopathy that may be an unrecognized curable cause of CHF (26)(27). Reducing the rapid ventricular rate by radiofrequency ablation of the AV node with permanent pacing caused an improvement in LVEF in patients with medically refractory AF (28). In a substudy of the Ablate and Pace Trial, 63 of 161 patients (39%) with AF referred for AV junction ablation and right ventricular pacing had an abnormal LVEF (29). Forty-eight of the 63 patients had follow-up echocardiograms. Sixteen of the 48 patients (33%) had a marked improvement in LVEF to a value higher than 45% after ventricular rate control by AV junction ablation (29).
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Clinical Symptoms
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Patients with AF may be symptomatic or asymptomatic with their arrhythmia detected by physical examination or by an ECG. Examination of a patient after a stroke may lead to the diagnosis of AF. Symptoms caused by AF may include palpitations, skips in heartbeat, fatigue on exertion, exercise intolerance, cough, chest pain, dizziness, and syncope. A rapid ventricular rate and loss of atrial contraction reduce cardiac output and may lead to angina pectoris, CHF, hypotension, acute pulmonary edema, and syncope, especially in patients with aortic stenosis, mitral stenosis, or hypertrophic cardiomyopathy.
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Diagnostic Tests
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When AF is suspected, a 12-lead ECG with a 1-minute rhythm strip should be obtained to confirm the diagnosis. If paroxysmal AF is suspected, a 24-hour ambulatory ECG should be obtained. All patients with AF should have an M-mode, two-dimensional, and Doppler echocardiogram to determine the presence and severity of the cardiac abnormalities causing AF and to identify risk factors for stroke. Appropriate tests for noncardiac causes of AF should be obtained when clinically indicated. Thyroid function tests should be obtained, as AF or CHF may be the only clinical manifestations of apathetic hyperthyroidism in older patients.
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Treatment of Underlying Causes
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Treatment of AF should include treatment of the underlying disease (such as hyperthyroidism, pneumonia, or pulmonary embolism) when possible. Surgical candidates for mitral valve replacement should undergo mitral valve surgery if it is clinically indicated. If mitral valve surgery is not performed in patients with significant mitral valve disease, elective cardioversion should not be attempted in patients with AF. Precipitating factors such as CHF, infection, hypokalemia, hypoglycemia, hypovolemia, and hypoxia should be treated immediately. Alcohol, coffee, and drugs (especially sympathomimetics) that precipitate AF should be avoided. Paroxysmal AF associated with the tachycardia-bradycardia (sick sinus sydrome) should be treated with permanent pacing in combination with drugs to slow a rapid ventricular rate associated with AF (30).
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Control of Very Rapid Ventricular Rate
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Direct-current (DC) cardioversion should be performed immediately in patients who have paroxysmal AF with a very rapid ventricular rate associated with an acute MI, chest pain caused by myocardial ischemia, hypotension, severe CHF, or syncope. Intravenous beta blockers (31)(32)(33)(34), diltiazem (35), or verapamil (36) may be used to slow immediately a very fast ventricular rate associated with AF.
Propranolol should be administered intravenously in a dose of 1.0 mg over a 5-minute period and then given intravenously at a rate of 0.5 mg/minute to a maximum dose of 0.1 mg/kg. Esmolol given intravenously in a dose of 0.5 mg/kg over 1 minute followed by 0.05 to 0.1 mg/kg per minute may also be used to slow a very rapid ventricular rate in AF. After the very rapid ventricular rate is slowed, oral propranolol should be started with an initial dose of 10 mg administered every 6 hours. This dose may be increased progressively to a maximum dose of 80 mg every 6 hours if necessary.
The initial dose of diltiazem given intravenously to slow a very fast ventricular rate in AF is 0.25 mg/kg given over 2 minutes. If this dose does not slow the very rapid ventricular rate and does not cause adverse effects, a second dose of 0.35 mg/kg given intravenously over 2 minutes should be administered 15 minutes after the first dose. After slowing the very rapid ventricular rate, oral diltiazem should be started with an initial dose of 60 mg given every 6 hours. If necessary, this dose may be increased to a maximum dose of 90 mg every 6 hours.
The initial dose of verapamil administered intravenously is 0.075 mg/kg (to a maximum dose of 5 mg). If this dose does not slow the very rapid ventricular rate and does not cause adverse effects, a second dose of 0.075 mg/kg (to a maximum dose of 5 mg) should be given intravenously 10 minutes after the first dose. If the second dose of intravenous verapamil does not slow the very rapid ventricular rate and does not cause adverse effects, a dose of 0.15 mg/kg (to a maximum dose of 10 mg) should be given intravenously 30 minutes after the second dose. After slowing the very rapid ventricular rate, oral verapamil should be started with an initial dose of 80 mg every 6 to 8 hours. This dose may be increased to 120 mg every 6 hours over the next 2 to 3 days.
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Control of Fast Ventricular Rate
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Digitalis glycosides are ineffective in converting AF to sinus rhythm (37). Digoxin is also ineffective in slowing a rapid ventricular rate in AF if there is associated fever, hyperthyroidism, acute blood loss, hypoxia, or any condition involving increased sympathetic tone (38). However, digoxin should be used to slow a fast ventricular rate in AF unassociated with increased sympathetic tone, hypertrophic cardiomyopathy, or the Wolff-Parkinson-White syndrome, especially if there is LV systolic dysfunction.
The usual initial dose of digoxin given to undigitalized patients with AF is 0.5 mg orally. Depending on the clinical response, a second oral dose of 0.25 mg may be administered in 6 to 8 hours, and a third oral dose of 0.25 mg may be given in another 6 to 8 hours to slow a rapid ventricular rate. The usual maintenance oral dose of digoxin administered to patients with AF is 0.25 mg to 0.5 mg daily, with the dose decreased to 0.125 mg to 0.25 mg daily for older patients who are more susceptible to digitalis toxicity (39).
Oral beta blockers (40), diltiazem (41), or verapamil (42) should be added to the therapeutic regimen if a fast ventricular rate in AF occurs at rest or during exercise despite digoxin. These drugs act synergistically with digoxin to depress conduction through the AV junction. In a study of atenolol 50 mg daily, digoxin 0.25 mg daily, diltiazem-CD 240 mg daily, digoxin 0.25 mg plus atenolol 50 mg daily, and digoxin 0.25 mg plus diltiazem-CD 240 mg daily, digoxin and diltiazem as single drugs were least effective and digoxin plus atenolol was most effective in controlling the ventricular rate in AF during daily activities (43).
Amiodarone is the most effective drug for slowing a rapid ventricular rate in AF (44)(45). However, its adverse effect profile limits its use in the treatment of AF. Oral doses of 200 mg to 400 mg of amiodarone daily may be administered to selected patients with symptomatic life-threatening AF refractory to other drugs.
Therapeutic concentrations of digoxin do not reduce the frequency of episodes of paroxysmal AF or the duration of episodes of paroxysmal AF diagnosed by 24-hour ambulatory ECGs (46)(47). Digoxin has been found to increase the duration of episodes of paroxysmal AF, a result consistent with its action in decreasing the atrial refractory period (46). Therapeutic concentrations of digoxin also do not prevent a rapid ventricular rate from developing in patients with paroxysmal AF (46)(47)(48). After a brief episode of AF, digoxin increases the shortening that occurs in atrial refactoriness and predisposes to the reinduction of AF (49). Therefore, digoxin should be avoided in patients with sinus rhythm with a history of paroxysmal AF.
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Nondrug Therapies
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Radiofrequency catheter modification of AV conduction should be performed in patients with symptomatic AF in whom a rapid ventricular rate cannot be slowed by drugs (50)(51). If this procedure does not control the rapid ventricular rate associated with AF, complete AV block produced by radiofrequency catheter ablation followed by permanent pacemaker implantation should be performed (52). In a randomized, controlled study of 66 persons with CHF and chronic AF, AV junction ablation with implantation of a VVIR pacemaker was superior to drug treatment in controlling symptoms (53). Long-term survival is similar for patients with AF whether they receive radiofrequency ablation of the AV node and implantation of a permanent pacemaker or drug therapy (54).
Surgical techniques have been developed for use in patients with AF in whom the ventricular rate cannot be slowed by drug treatment (55)(56). The maze procedure is a surgical dissection of the right and left atria, creating a maze through which the electrical activation is forced, preventing the formation and perpetuation of the multiple wavelets needed for maintenance of AF. This procedure is typically performed in association with mitral valve surgery or coronary artery bypass surgery. At 2 to 3 years of follow-up, 74% of 39 patients and 90% of 100 patients undergoing the maze procedure remained in sinus rhythm (57)(58). Thirty-five of 43 patients (85%) with drug-refractory, lone paroxysmal AF were arrhythmia free after maze surgery (59).
Another intraoperative approach for treating AF in patients undergoing mitral valve surgery is cryoablation limited to the posterior left atrium. Sinus rhythm was restored in 20 of 29 patients (69%) with chronic AF undergoing this procedure (60).
Ablation of pulmonary vein foci that cause AF is a developing area in the treatment of AF. However, recurrent AF develops in 40% to 60% of patients despite initial efficacy with this procedure (61). Another problem with this approach is a 3% incidence of pulmonary vein stenosis occurring after this procedure (61). Modification of the substrate responsible for AF can be accomplished in the right and/or left atrium with linear lesions. This catheter maze-ablation approach is effective in a small percentage of patients (62).
The Atrioverter (InControl, Redmond, WA), an implantable defibrillator connected to right atrial and right coronary sinus defibrillation leads, causes restoration of sinus rhythm by low-energy shock and has an 80% efficacy in terminating AF (63). Further efforts are needed to improve patient tolerability and to prevent earlier recurrence of AF after successful transvenous atrial defibrillation. The implanted atrial defibrillator is currently available only in combination with a ventricular defibrillator.
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Pacing
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Paroxysmal AF associated with the tachycardia-bradycardia (sick sinus) syndrome should be treated with a permanent pacemaker combined with drugs to decrease a fast ventricular rate associated with AF (30). Ventricular pacing is an independent risk factor for the development of chronic AF in patients with paroxysmal AF associated with the tachycardia-bradycardia syndrome (64). Patients with paroxysmal AF associated with the tachycardia-bradycardia syndrome and no signs of AV conduction abnormalities should be treated with atrial pacing or dual-chamber pacing rather than with ventricular pacing because atrial pacing is associated with less AF, fewer TE complications, and a lower risk of AV block than is ventricular pacing (65).
Many older patients are able to tolerate AF without the need for treatment because the ventricular rate is slow due to concomitant AV nodal disease. These patients should not be treated with drugs that depress AV conduction. A permanent pacemaker should be implanted in patients with AF who develop cerebral symptoms such as dizziness or syncope associated with ventricular pauses longer than 3 seconds that are not drug-induced, as documented by a 24-hour ambulatory ECG (66). If patients with AF have drug-induced symptomatic bradycardia, and the causative drug cannot be stopped, a permanent pacemaker must be implanted.
Atrial pacing is effective in treating vagotonic AF (67) and may be considered if treatment with a vagolytic antiarrhythmic drug such as disopyramide is ineffective. Atrial pacing is also effective in treating patients with the sick sinus syndrome (65). However, when bradycardia is not an indication for pacing, atrial-based pacing may not prevent episodes of AF (68). Dual-site atrial pacing is more efficacious than single-site pacing for preventing AF (69). However, the patients in this study had a bradycardia indication for pacing and continued to need antiarrhythmic drugs (69).
Dual-site atrial pacing with continued sinus overdrive for AF in patients with bradycardia prolonged time to AF recurrence and decreased AF burden in patients with paroxysmal AF (70). However, there was no difference in AF checklist symptom scores or overall quality-of-life scores (70). The absence of an effect on symptom control suggests that pacing should be used as adjunctive therapy with other treatment modalities for AF (70).
Biatrial pacing after coronary artery bypass surgery has also been shown to decrease the incidence of AF (71). All ECGs in patients with paced rhythm should be examined closely for underlying AF to prevent underrecognition of AF and undertreatment with anticoagulants (72).
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Wolff-Parkinson-White Syndrome
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DC cardioversion should be performed if a rapid ventricular rate in patients with paroxysmal AF associated with the Wolff-Parkinson-White syndrome is life-threatening or fails to respond to drug treatment. Drug therapy for paroxysmal AF associated with the Wolff-Parkinson-White syndrome includes propranolol plus procainamide, disopyramide, or quinidine (73). Digoxin, diltiazem, and verapamil are contraindicated in patients with AF with the Wolff-Parkinson-White syndrome because these drugs shorten the refractory period of the accessory AV pathway, resulting in more rapid conduction down the accessory pathway. This results in a marked increase in ventricular rate. Radiofrequency catheter ablation or surgical ablation of the accessory conduction pathway should be considered in patients with AF and rapid AV conduction over the accessory pathway (74). In 93% of 500 patients with an accessory pathway, radiofrequency catheter ablation of the accessory pathway was successful (75).
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Elective Cardioversion
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Elective DC cardioversion has a higher success rate than does medical cardioversion in converting AF to sinus rhythm (76). Table 3 shows favorable conditions for elective cardioversion of chronic AF. Table 4 shows unfavorable conditions for elective cardioversion of chronic AF.
The American College of Cardiology/American Heart Association/European Society for Cardiology guidelines state that Class I indications for cardioversion of AF to sinus rhythm include (i) immediate DC cardioversion in patients with paroxysmal AF and a rapid ventricular rate who have ECG evidence of acute MI or symptomatic hypotension, angina, or heart failure that does not respond promptly to pharmacological measures and (ii) DC or drug cardioversion in patients with chronic AF without hemodynamic instability when symptoms of AF are unacceptable (77).
Elective cardioversion of AF either by DC or by antiarrhythmic drugs should not be performed in asymptomatic older patients with chronic AF. Rectilinear, biphasic shocks have been shown to have greater efficacy and need less energy than the traditional damped sine wave monophasic shocks (78). Therefore, biphasic shocks to cardiovert AF should become the clinical standard.
Antiarrhythmic drugs that have been used to convert AF to sinus rhythm include amiodarone, disopyramide, dofetilide, encainide, flecainide, ibutilide, procainamide, propafenone, quinidine, and sotalol. None of these drugs is as successful as DC cardioversion, which has a success rate of 80% to 90% in converting AF to sinus rhythm. All of these drugs are proarrhythmic and may aggravate or cause cardiac arrhythmias.
Encainide and flecainide caused atrial proarrhythmic effects in six of 60 patients (10%) (79). The atrial proarrhythmic effects included conversion of AF to atrial flutter with a 1-to-1 AV conduction response and a very rapid ventricular rate (79). Flecainide has caused ventricular tachycardia and ventricular fibrillation in patients with chronic AF (80). Antiarrhythmic drugs including amiodarone, disopyramide, flecainide, procainamide, propafenone, quinidine, and sotalol caused cardiac adverse effects in 73 of 417 patients (18%) hospitalized for AF (81). Class IC drugs such as encainide, flecainide, and propafenone should not be used in patients with prior MI or abnormal LVEF because these drugs may cause life-threatening ventricular tachyarrhythmias in these patients (82).
Dofetilide and ibutilide are Class III antiarrhythmic drugs that have been used for the conversion of AF to sinus rhythm. Eleven of 75 patients (15%) with AF treated with intravenous dofetilide converted to sinus rhythm (83). Torsade de pointes occurred in 3% of patients treated with intravenous dofetilide (83). After 1 month, 22 of 190 patients (12%) with AF and CHF had sinus rhythm restored with dofetilide compared to three of 201 patients (1%) treated with placebo (84). Torsade de pointes developed in 25 of 762 patients (3%) treated with dofetilide and in none of 756 patients (0%) treated with placebo (84). Twenty-three of 79 patients (29%) with AF treated with intravenous ibutilide converted to sinus rhythm (85). Polymorphic ventricular tachycardia developed in 4% of patients who received intravenous ibutilide in this study (85).
DC cardioversion of AF has a higher success rate in converting AF to sinus rhythm and a lower incidence of cardiac adverse effects than treatment with any antiarrhythmic drug. However, pretreatment with ibutilide has been found to facilitate transthoracic cardioversion of AF (86).
Unless transesophageal echocardiography has demonstrated no thrombus in the left atrial appendage before cardioversion (87), oral warfarin should be given for 3 weeks before elective DC or drug conversion of patients with AF to sinus rhythm (88). Anticoagulant therapy should also be used at the time of cardioversion and continued until sinus rhythm has been maintained for 4 weeks (88). After DC or drug cardioversion of AF to sinus rhythm, the left atrium becomes stunned and contracts poorly for 3 to 4 weeks, predisposing to TE stroke unless the patient is maintained on oral warfarin (89)(90). The maintenance dose of oral warfarin should be titrated by serial prothrombin times so that the International Normalized Ratio (INR) is 2.0 to 3.0 (88).
In a multicenter, randomized, prospective study, 1222 patients with AF of more than 2 days of duration were randomized to either treatment guided by the findings on transesophageal echocardiography or to treatment with conventional therapy (91). The primary endpoint was cerebrovascular accident, transient ischemic attack, and peripheral embolism within 8 weeks. The incidence of embolic events at 8 weeks was 0.8% in the transesophageal echocardiography treatment group and 0.5% in the conventional treatment group (91). At 8 weeks, there were also no significant differences between the two groups in the rates of death, maintenance of sinus rhythm, or functional status (91). However, there was a trend toward a higher rate of death from any cause in the transesophageal echocardiography treatment group (2.4%) than in the conventional treatment group (1.0%) (p = .06) (91).
This study showed the importance of maintaining therapeutic anticoagulation in the period after cardioversion even if there is no transesophageal echocardiographic evidence of thrombus (90)(92). The best treatment strategy for patients with evidence of an atrial thrombus on initial transesophageal echocardiography remains controversial (93). In the absence of data from a randomized trial, patients probably should have follow-up transesophageal echocardiography after 1 month of warfarin therapy to document resolution of the atrial thrombus (93)(94).
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Use of Antiarrhythmic Drugs to Maintain Sinus Rhythm
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The efficacy and safety of antiarrhythmic drugs after cardioversion of AF to maintain sinus rhythm have been questioned. A meta-analysis of six double-blind, placebo-controlled studies of quinidine involving 808 patients who had direct-current cardioversion of chronic AF to sinus rhythm showed that 50% of patients treated with quinidine and 25% of patients treated with placebo remained in sinus rhythm at 1 year of follow-up (95). However, the mortality was significantly higher in patients treated with quinidine (2.9%) than in patients treated with placebo (0.8%) (95). In a study of 406 patients with a mean age of 82 years with heart disease and complex ventricular arrhythmias, the incidence of adverse effects causing drug cessation was 48% for quinidine and 55% for procainamide (96). The incidence of total mortality at the 2-year follow-up was insignificantly higher in patients treated with quinidine or procainamide compared with patients not receiving an antiarrhythmic drug (96).
In another study, 85 patients were randomized to quinidine and 98 patients to sotalol after DC cardioversion of AF to sinus rhythm (97). At the 6-month follow-up, 48% of quinidine-treated patients and 52% of sotalol-treated patients remained in sinus rhythm (97). At 1-year follow-up of 100 patients with AF cardioverted to sinus rhythm, 37% of 50 patients randomized to sotalol and 30% of 50 patients randomized to propafenone remained in sinus rhythm (98).
In a study of 403 patients with at least one episode of AF in the prior 6 months, 201 patients were treated with amiodarone, and 202 patients were treated with sotalol or propafenone (99). At the 16-month follow-up, AF recurred in 35% of patients treated with amiodarone and in 63% of patients treated with sotalol or propafenone (99). Adverse effects causing discontinuation of drug occurred in 18% of patients treated with amiodarone and in 11% of patients treated with sotalol or propafenone (99).
After cardioversion of 394 patients with AF to sinus rhythm, 197 patients were randomized to metoprolol CR/XL and 197 patients to placebo (100). At the 6-month follow-up, the percentage of patients in sinus rhythm was significantly higher on metoprolol CR/XL (51%) than on placebo (40%) (100). The heart rate in patients who relapsed into AF was also significantly lower in patients treated with metoprolol CR/XL than in patients treated with placebo (100).
In a study of 384 patients with a history of AF or atrial flutter, azimilide lengthened the median time to first symptomatic arrhythmia recurrence from 17 days in the placebo group to 60 days in the azimilide group (101). However, additional data on both efficacy and safety of azimilide are necessary before knowing its role in clinical practice.
Of the 1330 patients in the Stroke Prevention in Atrial Fibrillation (SPAF) Study, 127 persons were taking quinidine, 57 procainamide, 34 flecainide, 20 encainide, 15 disopyramide, and seven amiodarone (102). Patients who were taking an antiarrhythmic drug had a 2.7 times higher adjusted relative risk of cardiac mortality and a 2.3 times higher adjusted relative risk of arrhythmic death compared with patients not taking an antiarrhythmic drug (102). Patients with a history of CHF who were taking an antiarrhythmic drug had a 4.7 times higher relative risk of cardiac death and a 3.7 times higher relative risk of arrhythmic death than patients with a history of CHF not taking an antiarrhythmic drug (102).
A meta-analysis of 23,229 patients in 59 randomized, controlled trials that investigated the use of aprindine, disopyramide, encainide, flecainide, imipramine, lidocaine, mexiletine, moricizine, phenytoin, procainamide, quinidine, and tocainide after MI also demonstrated that mortality was significantly higher in patients receiving Class I antiarrhythmic drugs (odds ratio = 1.14) than in patients not receiving an antiarrhythmic drug (103). None of the 59 studies showed a reduction in mortality by antiarrhythmic drugs (103).
Amiodarone is the antiarrhythmic drug with the highest success rate in maintenance of sinus rhythm after cardioversion of AF (99). However, in the Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation Study, the incidence of pulmonary toxicity was 10% at 2 years in patients receiving amiodarone in a mean dose of 158 mg daily (104). The incidence of adverse effects from amiodarone also approaches 90% after 5 years of therapy (105).
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Ventricular Rate Control
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Because maintenance of sinus rhythm with antiarrhythmic drugs may require serial cardioversions; exposes patients to the risks of proarrhythmia, sudden cardiac death, and other adverse effects; and requires the use of anticoagulants in patients in sinus rhythm who have a high risk of recurrence of AF, many cardiologists, including myself, prefer the treatment strategy of ventricular rate control plus use of anticoagulants in patients with AF, especially in older patients with AF. Beta blockers such as propranolol 10 mg to 30 mg given three to four times daily can be administered to control ventricular arrhythmias (106) and after conversion of AF to sinus rhythm. Should AF recur, beta blockers have the added advantage of slowing the ventricular rate. Beta blockers are also the most effective drugs in preventing and treating AF after coronary artery bypass surgery (107).
The Pharmacological Intervention in Atrial Fibrillation trial was a randomized trial of 252 patients with AF of between 7 days' and 360 days' duration that compared rate control (125 patients) with rhythm control (127 patients) (108). Diltiazem was used as first-line treatment in patients randomized to rate control. Amiodarone was used as first-line treatment in patients randomized to rhythm control. Amiodarone administration resulted in conversion of 23% of patients to sinus rhythm (108). Symptomatic improvement was reported in a similar percentage of patients in both groups. Assessment of quality of life showed no significant difference between the two treatment groups. The incidence of hospital admission was significantly higher in patients treated with rhythm control (69%) than in patients treated with rate control (24%) (108). Adverse drug effects caused a change in drug therapy in significantly more patients treated with rhythm control (25%) than in patients treated with rate control (14%) (108).
The Atrial Fibrillation Follow-Up Investigation of Rhythm Management Study randomized patients with paroxysmal or chronic AF of less than 6 months of duration at high risk for stroke to either maintenance of AF with ventricular rate control or to an attempt to maintain sinus rhythm with antiarrhythmic drugs after cardioversion (109). Patients in both arms of this study were treated with warfarin. The primary endpoint of this study is total mortality. Preliminary results from this study were reported at the Annual Scientific Meeting of the American College of Cardiology in Atlanta, Georgia, in March 2002 (see Addendum).
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Risk Factors for Thromboembolic Stroke
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Table 5 shows risk factors for TE stroke in patients with AF (1)(2)(21)(110)(111)(112)(113)(114)(115)(116)(117)(118)(119)(120). In the SPAF Study involving patients with a mean age of 67 years, recent CHF (within 3 months), a history of hypertension, previous thromboembolism, echocardiographic left atrial enlargement, and echocardiographic LV systolic dysfunction were associated independently with the development of new TE events (114)(117). The incidence of new TE events was 18.6% per year if three or more risk factors were present, 6.0% per year if one or two risk factors were present, and 1.0% per year if none of these risk factors was present (114).
In the SPAF III Study involving patients with a mean age of 72 years, patients were considered at high risk for developing TE stroke if they had either prior thromboembolism, CHF or abnormal LV systolic function, a systolic blood pressure of greater than 160 mm Hg, or if the patient was a woman older than 75 years of age (115). In a study of 312 patients with chronic AF with a mean age of 84 years, independent risk factors for the development of new TE stroke were prior stroke (risk ratio = 1.6), rheumatic mitral stenosis (risk ratio = 2.0), LVH (risk ratio = 2.8), abnormal LVEF (risk ratio = 1.8), serum total cholesterol (risk ratio = 1.01 per 1 mg/dL increase), serum high-density lipoprotein cholesterol (risk ratio = 1.04 per 1 mg/dL decrease), and age (risk ratio = 1.03 per 1 year increase) (112).
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Antithrombotic Therapy
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Prospective, randomized trials (110)(115)(120)(121)(122)(123)(124)(125)(126)(127) and prospective, nonrandomized observational data from patients with mean ages of 83 years (116) and 84 years (128) have demonstrated that warfarin is effective in reducing the incidence of TE stroke in patients with nonvalvular AF. Analysis of pooled data from five randomized, placebo-controlled studies demonstrated that warfarin significantly decreased the incidence of new TE stroke by 68% and was significantly more effective than aspirin in decreasing the incidence of new TE stroke (111). In the Veterans Affairs Cooperative study, the incidence of new TE events was 4.3% per year in patients on placebo versus 0.9% per year in patients on warfarin in patients with no prior stroke, 9.3% per year in patients on placebo versus 6.1% per year in patients on warfarin in patients with prior stroke, and 4.8% per year in patients on placebo versus 0.9% per year in patients on warfarin in patients older than 70 years of age (125). In the European Atrial Fibrillation Trial involving patients with recent transient cerebral ischemic attack or minor ischemic stroke, at 2.3 years of follow-up, the incidence of new TE events was 12% per year in patients taking placebo, 10% per year in patients taking aspirin, and 4% per year in patients taking warfarin (120).
Nonrandomized observational data from older patients with chronic AF with a mean age of 83 years showed that 141 patients treated with oral warfarin to achieve an INR between 2.0 and 3.0 (mean INR was 2.4) had a 67% significant reduction in new TE stroke compared with 209 patients treated with oral aspirin (116). Compared with aspirin, warfarin caused a 40% significant decrease in new TE stroke in patients with prior stroke, a 31% significant decrease in new TE stroke in patients with no prior stroke, a 45% significant decrease in new TE stroke in patients with abnormal LVEF, and a 36% significant decrease in new TE stroke in patients with normal LVEF (116).
At the 1.1-year follow-up in the SPAF III Study, patients with AF considered to be at high risk for developing new TE stroke who were randomized to treatment with oral warfarin to achieve an INR between 2.0 and 3.0 had a 72% significant reduction in ischemic stroke or systemic embolism compared with patients randomized to treatment with oral aspirin 325 mg daily plus oral warfarin to achieve an INR between 1.2 and 1.5 (115). Adjusted-dose warfarin caused an absolute reduction in ischemic stroke or systemic embolism of 6.0% per year (115). In the Second Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation (AFASK) Study, low-dose warfarin plus aspirin was also less effective in decreasing stroke or systemic TE events in patients with AF (7.2% after 1 year) than was adjusted-dose warfarin to achieve an INR between 2.0 and 3.0 (2.8% after 1 year) (127).
Analysis of pooled data from five randomized controlled studies demonstrated that the annual incidence of major hemorrhage was 1.0% for the control group, 1.0% for the aspirin group, and 1.3% for the warfarin group (111). The incidence of major hemorrhage in patients with a mean age of 72 years who were taking adjusted-dose warfarin to achieve an INR of 2.0 to 3.0 in the SPAF III Study was 2.1% (115). In the Second Copenhagen AFASK Study, the incidence of major hemorrhage in patients with a mean age of 73 years was 0.8% per year for patients treated with adjusted-dose warfarin to achieve an INR between 2.0 and 3.0 and 1.0% per year for patients treated with aspirin 300 mg daily (127). The incidence of major hemorrhage in older patients with chronic AF with a mean age of 83 years was 4.3% (1.4% per year) in patients treated with warfarin to maintain an INR between 2.0 and 3.0 and 2.9% (1.0% per year) in patients treated with aspirin 325 mg daily (116).
In the SPAF III Study, 892 patients with a mean age of 67 years who were at low risk for developing TE stroke were treated with oral aspirin 325 mg daily (129). The incidence of ischemic stroke or systemic embolism was 2.2% per year (129). The incidence of ischemic stroke or systemic embolism was 3.6% per year in patients with a history of hypertension and 1.1% per year in patients with no history of hypertension (129).
On the basis of the available data, patients with chronic or paroxysmal AF at high risk for developing TE stroke or with a history of hypertension and who have no contraindications to anticoagulation therapy, including a history of falls, should be treated with long-term oral warfarin to achieve an INR between 2.0 and 3.0 (88). Hypertension must be controlled. Whenever the patient has a prothrombin time taken, the blood pressure should also be checked. The physician prescribing warfarin should be aware of the numerous drugs that potentiate the effect of warfarin causing an increased prothrombin time and risk of bleeding (130). Patients with AF at low risk for developing TE stroke or with contraindications to treatment with long-term oral warfarin should be treated with aspirin 325 mg orally daily (131).
Patients younger than 60 years of age in Olmstead County, Minnesota, with lone AF (no heart disease) had a low risk of TE stroke at the 15-year follow-up (132). However, at the 30-year follow-up in the Framingham Heart Study, the age-adjusted percentage of patients with lone AF who developed a cerebrovascular event was 28% versus 7% in the control group (133). Table 6 shows the American College of Cardiology/American Heart Association/European Society for Cardiology Class I indications for antithrombotic therapy in the treatment of patients with AF (77).
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Table 6. American College of Cardiology/American Heart Association/European Society for Cardiology Class I Indications for Treating Patients With Atrial Fibrillation With Antithrombotic Therapy
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Despite the data showing the efficacy of oral warfarin used in a dose to achieve an INR between 2.0 and 3.0 in decreasing the incidence of new TE events in patients with paroxysmal or chronic AF, only about one third of patients with AF who should be taking warfarin receive it (134). In an academic hospital-based geriatrics practice, only 61 of 124 patients (49%) with a mean age of 80 years with chronic AF at high risk for developing TE stroke and no contraindications to warfarin were receiving warfarin therapy (5).
Older patients have a higher prevalence and incidence of AF than younger patients (1)(2)(3)(4)(5)(6). Older patients with AF are at greater risk for developing TE stroke than are younger patients with AF (1)(19)(110)(111)(112). However, physicians are more reluctant to treat older patients with AF with warfarin therapy. Hopefully, intensive physician education will help solve this important clinical problem.
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Addendum
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The following data were presented at a Late Breaking Clinical Trial Session by George Wyse, MD, on behalf of the AFFIRM investigators at the Annual Scientific Meeting of the American College of Cardiology in Atlanta, Georgia, on March 18, 2002: At 3.5-year mean follow-up in the AFFIRM Study, compared to the maintenance of sinus rhythm group, the ventricular rate control group had an insignificant reduction in all-cause mortality (306 vs 356 deaths, p = .058), an insignificant reduction in stroke (5.7% vs 7.3%), a significant reduction in the number of patients hospitalized (70% vs 78%, p < .0001), and no significant difference in quality of life or functional status.
Received December 19, 2001
Accepted January 3, 2002
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Abstract
Prevalence