Brevibloc

Atrial fibrillation affects more than 1 million Americans each year. The prevalence of this disorder ranges from 0.004 percent in patients 15 to 50 years of age[1] to at least 5 percent in those over 75 years of age.[2] A recent study[3] identified diabetes, hypertension, congestive heart failure, left ventricular hypertrophy, a history of myocardial infarction, valvular heart disease and male gender, in addition to age, as risk factors for the development of atrial fibrillation.

Atrial fibrillation has traditionally been treated with digitalis. However, the management of this disorder is evolving due to the findings of recently published studies.

Pathophysiology

Atrial fibrillation is a rhythm disturbance characterized by chaotic atrial electrical activity and, consequently, no mechanically effective atrial contraction. Random arrival of electrical signals at the atrioventricular node produces ventricular contraction with no discernible periodicity. Atrial fibrillation may be chronic or intermittent (paroxysmal atrial fibrillation).

The pulse in cases of atrial fibrillation has irregular timing and amplitude, and the electrocardiogram shows irregular R-R intervals with no identifiable P waves. Patients may experience fatigue because the rhythm disturbance impairs cardiac output, or they may have palpitations because the irregular pulse causes some beats to have large stroke volumes.

Many conditions cause atrial fibrillation (Table 1). Underlying most of these causes is an elevation of left or right atrial pressure; the mechanism by which atrial hypertension produces electrical instability is not known. In addition, toxic or metabolic problems, such as excessive alcohol consumption or hyperthyroidism, can cause atrial fibrillation. Sometimes no cause is identifiable, and the patient is said to have "lone atrial fibrillation."

Management of Unstable

or Complicated Atrial Fibrillation

As a consequence of the rapid heart rate or the loss of atrial contribution to ventricular filling associated with atrial fibrillation, patients may develop acute hypotension, angina or heart failure. In such cases, immediate direct-current cardioversion is indicated, and patients should be hospitalized. Since cardioversion is a painful procedure, anesthesia or sedation is necessary in all but the most serious emergency situation. Nasal oxygen is a useful adjuvant therapy. Emergency anesthesiology consultation is suggested.

After cardioversion, patients should be hospitalized and their cardiac rhythm stabilized. Rhythm stabilization is best accomplished with intravenous procainamide (Pronestyl), followed by oral maintenance therapy (Procan). These potentially unstable patients should also receive maintenance digoxin (Lanoxin) or a beta blocker. Suggested dosages of these agents are given in Table 2.

[TABULAR DATA OMITTED]

Initial Management

of Uncomplicated Atrial Fibrillation

RATE CONTROL

Control of the ventricular response is the first issue in patients who do not require immediate cardioversion (Figure 1). Patients who develop atrial fibrillation as a consequence of severe systemic disease may have a rapid heart rate related to that disease. If the physician believes that a patient would have tachycardia if his or her cardiac rhythm were sinus, it would not be appropriate to bring the ventricular rate below 100.

Digoxin has traditionally been used to control the ventricular response in patients who have atrial fibrillation, but recent evidence suggests that beta blockers should receive first consideration. One reason is that digoxin does not promote conversion to normal sinus rhythm.[4] In contrast, beta blockers may have such an effect. One study-5 found that conversion to normal sinus rhythm occurred in 50 percent of patients who received intravenous esmolol (Brevibloc).

Onset of action is another reason for considering the initial use of beta blockers. Digoxin is relatively slow-acting, since significant levels of the drug must be present in myocardial tissue before slowing of atrioventricular conduction occurs. Even with intravenous loading, slowing of the heart rate takes approximately six hours.[4] In contrast, the heart rate may decrease within minutes after the administration of a beta blocker.

Finally, digoxin does not appear to be appropriate for maintenance therapy in patients with paroxysmal atrial fibrillation. The drug does not reduce the frequency of attacks[6] and does not reduce the heart rate when paroxysms occur.[7]

Beta-blocker therapy is contraindicated in patients who have asthma, obstructive lung disease or left ventricular systolic dyfunction. The calcium channel blockers verapamil (Calan, Isoptin) and diltiazem (Cardizem) are appropriate therapeutic options for patients with asthma or obstructive lung disease, while digoxin should be used in patients with ventricular systolic dysfunction.

Calcium channel blockers are alternative agents for controlling the ventricular response. Although intravenous verapamil is effective, it has a short duration of action. Consequently, the drug must be given in a continuous infusion, or doses must be repeated every 15 to 20 minutes. Since intravenous diltiazem has a longer duration of action than verapamil, it is a good alternative to one of the intravenously administered beta blockers.

Digoxin may still be useful in patients with left ventricular systolic dysfunction when the drug is to be used for its inotropic effect and its delayed onset of action is not considered to be a problem. Digoxin may be less effective when hypomagnesemia is present.[8] Therapy for magnesium deficiency should be considered when the ventricular rate is refractory to digoxin.

Digoxin is not useful, and may be harmful, in patients with left ventricular diastolic dysfunction. Examples of diseases in which diastolic dysfunction may be present are hypertensive heart disease and hypertrophic cardiomyopathy. Beta blockers or calcium channel blockers are the preferred agents in patients with diastolic dysfunction.

In one report,[9] oral clonidine (Catapres) loading controlled the ventricular rate. The results of this study have yet to be confirmed.

When atrial fibrillation occurs in patients with Wolff-Parkinson-White syndrome, digoxin, beta blockers and calcium blockers may paradoxically increase the heart rate and precipitate ventricular fibrillation. Such patients should be managed with cardioversion or intravenous procainamide.

The characteristics of agents that are useful in controlling ventricular rate in atrial fibrillation are compared in Table 3. Dosing schedules for these drugs are given in Table 2.

[TABULAR DATA OMITTED]

DIAGNOSTIC EVALUATION

Once the ventricular rate has been controlled, it is important to identify the cause of the atrial fibrillation. A routine clinical evaluation, consisting of a careful history, a thorough physical examination, standard screening laboratory tests, an electrocardiogram and a chest radiograph, will identify most of the systemic diseases that cause atrial fibrillation. The history should include a careful assessment for alcoholism and binge drinking.[10,11]

The routine evaluation may miss hyperthyroidism, especially in the aged. Therefore, thyroid function tests should be ordered routinely.

If no underlying systemic disease or metabolic abnormality is noted, an echocardiogram should be performed to detect any underlying structural heart disease.

CRITERIA FOR HOSPITALIZATION

Outpatient management of atrial fibrillation should be considered when the ventricular rate can be controlled in patients who do not have hypotension, angina or heart failure at the time of presentation.

Because atrial fibrillation frequently occurs in patients with coronary artery disease, many physicians have felt obliged to admit patients with new-onset atrial fibrillation to a coronary care unit in order to rule out myocardial infarction. However, two studies[12,13] that addressed this issue found that routine admission was not warranted. Patients who were subsequently shown to have had a myocardial infarction had typical chest pain or left ventricular hypertrophy, ST-T changes or Q waves consistent with myocardial infarction.

Patients with congestive heart failure, known coronary disease or hemodynamic dependence on atrial contraction[14,15] are at risk for adverse outcomes and therefore should be hospitalized. Patients who are dependent on atrial contraction for ventricular filling include those with significant mitral stenosis, aortic stenosis or hypertrophic cardiomyopathy. Hospitalization is also appropriate for patients who still have symptoms after the ventricular rate is controlled.

Intermediate Management

of Uncomplicated Atrial Fibrillation

CONSIDERATION OF CARDIOVERSION

After the ventricular rate has been controlled and the diagnostic evaluation has been performed, electrical cardioversion should be considered in all patients, including those who have not been admitted to the hospital. There are two advantages to the restoration of sinus rhythm. The first advantage is that restoring normal sinus rhythm may improve functional capacity. One study[16] found that the anaerobic threshold improved by 14 percent following cardioversion in patients with chronic atrial fibrillation. Patients with the poorest functional capacity while in atrial fibrillation had the greatest degree of improvement after cardioversion. The second advantage to restoring sinus rhythm relates to the fact that chronic atrial fibrillation is associated with systemic embolization, and many patients in atrial fibrillation require anticoagulation. Restoration of normal sinus rhythm makes lifelong prescription of anticoagulant drugs unnecessary.

The advantages of cardioversion must be balanced against the fact that many patients revert to atrial fibrillation. Several factors, however, identify patients who are unlikely to remain in sinus rhythm.[17,18] The most important factor is duration of fibrillation. In one study,[17] 67 percent of patients with atrial fibrillation of less than three months' duration remained in sinus rhythm six months after cardioversion. When atrial fibrillation had been present for more than one year, the six-month success rate fell to 27 percent.

Left atrial dimension by echocardiography was previously cited as a predictor of successful cardioversion. However, its size is probably not as important as originally thought, since left atrial dilation occurs as a consequence of longstanding atrial fibrillation.19 Instead, duration of arrhythmia is the critical variable.

Other factors associated with lower success rates for cardioversion include uncorrected mitral valve disease, cardiomyopathy and advanced pulmonary disease. Ongoing binge alcohol drinking is also a factor.[11]

ANTICOAGULATION

Since emboli can occur after cardioversion, even when atrial fibrillation has been present for only a few days,[20] all patients should be anticoagulated before the procedure is performed. The duration of anticoagulation is not well established. Hospitalized patients should receive heparin for at least 48 hours before cardioversion,[21] and outpatients should receive warfarin (Coumadin) for two to three weeks before the procedure.

After successful cardioversion, oral anticoagulants should be continued for three weeks, because atrial contraction does not necessarily begin when atrial electrical activity does.[22,23] During this interval, the hypocontractile atria may continue to be a substrate for thrombus formation.

ANTIARRHYTHMIC DRUG THERAPY

After 48 hours of heparin therapy or two to three weeks of warfarin therapy, antiarrhythmic drug therapy should be initiated (Tables 2 and 4). In patients receiving treatment on an outpatient basis, QRS and QT intervals should be assessed two or three days after initiation of antiarrhythmic drug therapy.

[TABULAR DATA OMITTED]

Quinidine (Quinaglute) is the traditional antiarrhythmic drug of choice, but procainamide, disopyramide (Norpace), flecainide (Tambocor), propafenone (Rythmol), sotalol (Betapace) and amiodarone (Cordarone) also have been used. Moricizine (Ethmozine) should not be used, since it has not been adequately evaluated in patients with atrial fibrillation. Disopyramide should be used only as a second-line agent, since it has an adverse side effect profile.

The Class Ic agents - flecainide and propafenone - should be used with caution because of their association with serious proarrhytmic effects. One study revealed that encainide or flecainide resulted in an increase in cardiac deaths among patients who were being treated for frequent premature ventricular contractions following myocardial infarction.[24] Life-threatening arrhythmias have been observed when flecainide was used to treat atrial fibrillation in patients with structurally normal hearts.[25]

No controlled studies have been published describing the use of low-dose amiodarone following cardioversion, but many cardiologists believe this drug has advantages over other antiarrhythmic agents.[26] Amiodarone appears to maintain sinus rhythm more frequently and to have fewer proarrhythmic effects than the other available agents. At this time, consultation with a cardiologist is necessary before amiodarone is used to treat atrial fibrillation.

If antiarrhythmic therapy alone fails to convert the cardiac rhythm to sinus, serum levels of the agent should be measured. If the serum level is therapeutic, a second drug trial can be considered, since 20 to 40 percent of patients who do not convert on one agent may convert on another drug. In one study,[27] for example, approximately 40 percent of the patients initially tried on quinidine or procainamide were successfully treated with propafenone. After one or more drugs have been unsuccessful in converting the rhythm to sinus, cardioversion should be performed.

CARDIOVERSION

Not only is cardioversion used as an emergency procedure in patients who are unstable because of atrial fibrillation, but it is also used when antiarrhythmic drugs have failed to convert established atrial fibrillation in stable patients.

If the physician decides to proceed with cardioversion, the protocol outlined in Figure 2 should be followed closely. Since digitalis toxicity may predispose patients to ventricular fibrillation during electrical cardioversion, the digoxin level should be checked before the procedure is performed. An electrolyte imbalance, especially a low potassium level, should be excluded.

Outpatients may be admitted the morning of the procedure. For all elective cardioversions, it is suggested that an anesthesiologist be present to administer short-acting barbiturates and/or benzodiazepines and to manage any problems with the airways. Conversion usually can be accomplished with 50 to 100 joules (J), but up to 360 J may be required. Energy requirements may be reduced by placing one electrode anteriorly and one posteriorly on the left side of the chest. Patients may be discharged six hours after cardioversion.

Long-Term Management

ANTICOAGULATION

When a decision has been made not to proceed with cardioversion or when cardioversion is unsuccessful, a wealth of recent infomation[28-32] favors the long-term use of anticoagulant therapy to reduce the risk of cerebral embolus formation. In patients with nonrheumatic atrial fibrillation, the risk for stroke is approximately 5 percent per patient per year.

In five randomized trials of anticoagulant therapy,[28-32] event rates in patients who were given anticoagulant drugs ranged from 0.9 to 3.5 percent and were significantly lower than the rates in patients who were given placebo. The incidence rates for major bleeding episodes ranged from zero to 0.9 percent in patients who were given placebo and from 2.5 to 6.0 percent in patients who were treated with anticoagulant drugs.[28-32] The trials did not exclude the elderly, and it appears that age alone should not keep patients from receiving anticoagulant therapy. One study[16] found that the mortality rate was lower in patients who received warfarin.

The intensity of anticoagulation varied among the studies. In the Veterans Affairs study,[32] patients were maintained at prothrombin time ratios of 1.2 to 1.5. (It is expected that in years to come the International Normalized Ratio [INR] will be increasingly used to report prothrombin time results m the United States. INR values of 1.4 to 2.8 were found to be effective.[32]) Despite the low level of anticoagulation, a decrease in the rate of cerebral infarction was noted, which suggests that low-dose anticoagulation should be standard therapy in patients with atrial fibrillation.

ASPIRIN

The Danish Atrial Fibrillation, Aspirin, Anticoagulation Study[28] compared warfarin and aspirin and showed a benefit with warfarin. In this study, 1,007 patients were randomized to receive aspirin (75 mg per day), warfarin or placebo. The yearly incidence of thromboemboli was 2 percent in the patients who were treated with warfarin, but 5.5 percent in the patients who received aspirin or placebo. The difference for warfarin versus either aspirin or placebo was statistically significant. There were 21 bleeding episodes in the patients who were treated with warfarin, and there were two bleeding episodes in those who received aspirin; no episodes were fatal. Three vascular deaths occurred in the patients who received warfarin, but 12 deaths occurred m those who were given aspirin. (Vascular death was defined as mortality resulting from myocardial infarction, cerebral infarction or visceral embolus.) The low dose of aspirin used in the study may have been responsible for the lack of efficacy of the drug.

In the Stroke Prevention in Atrial Fibrillation 11 Study,[33] 1,100 patients were randomized to receive either enteric-coated aspirin (325 mg per day) or warfarin adjusted to an INR of 2.0 to 4.5. Patients were stratified by age over 75 and age 75 or younger. For patients 75 or less, the yearly rate of stroke or embolus was 1.3 percent with warfarin and 1.9 percent with aspirin. For patients older than 75, the rates were 3.6 percent for warfarin and 4.8 percent for aspirin. The differences between the two groups were not statistically significant, and the study appears to show no benefit for warfarin over aspirin. The investigators also analyzed the data by risk factors for stroke, including hypertension, heart failure and a history of embolus (Table 5). Although the differences between warfarin and aspirin were greater when risk factors were present, these differences were still not statistically significant. Details of the study design[34] need to be taken into account, however.

[TABULAR DATA OMITTED]

The study sample size was based on an expected event rate of 3.3 percent in the younger patients on aspirin and 9.0 percent in the older patients. The investigators made the judgment that warfarin would have to reduce these rates to 1.3 percent and 5.0 percent, respectively, in order to justify the risk and cost of lifelong anticoagulation. Because the observed rates of embolus were lower than the expected rates, more patients would have to have been-enrolled to detect a statistically significant difference between warfarin and aspirin.

In summary, warfarin lowers the risk of embolus 40 percent more than aspirin does. In patients at low risk for embolus, this reduction does not justify the risks associated with lifelong anticoagulation.

IDENTIFYING RISK OF STROKE

Based on a recent analysis,[35] it is possible to identify patients at low risk of embolus. Data from five studies[28-32] were pooled and multivariate analysis was used to identify risk factors for stroke in patients with atrial fibrillation. The risk factors identified were increasing age, previous stroke or transient ischemic attack, history of hypertension and diabetes. The type of fibrillation (paroxysmal or chronic) had no effect on the stroke rate. In patients younger than 65 years of age and without a history of prior embolus, hypertension or diabetes, the annual stroke rate was very low (1.0 percent) and unchanged with warfarin therapy; such patients should not receive anticoagulant therapy. All others should. The role of aspirin may be expanded by the results of ongoing studies.

Atrial fibrillation caused by hyperthyroidism represents a special high-risk case in which anticoagulation probably should be used.[36]

ANTIARRHYTMIC THERAPY

Guidelines for the duration of antiarrhythmic drug therapy are not firmly based. It is becoming increasingly clear that the benefits of antiarrhythmic drugs need to be balanced against their tendency to cause life-threatening arrhythmias. In an analysis of pooled data from six trials,[37] the overall mortality rate was 2.8 percent in patients who were treated with quinidine after cardioversion and 0.8 percent in patients who did not receive antiarrhythmic drugs. Antiarrhythmic therapy should not be used indefinitely following cardioversion; whenever possible, the drug should be withdrawn after two to three months.

Transcatheter atrioventricular nodal ablation with permanent pacer implant is an option for the rare symptomatic patient who is refractory to all other forms of therapy.

Final Comment

The management of patients with atrial fibrillation is evolving as a result of a number of recently published studies. Beta blockers are emerging as better choices for rate control than digoxin. Patients at high risk for adverse outcomes need to be identified and hospitalized for treatment, but low-risk patients can be managed on an outpatient basis. A search for the underlying cause of atrial fibrillation remains appropriate, and cardioversion should be considered in afl patients. Patients without risk factors for systemic embolus should be treated with aspirin, and patients with risk factors should be treated with anticoagulant drugs. Long-term antiarrhythmic therapy should be approached cautiously, because the proarthythmic effects of these drugs may increase mortality in patients who receIve them.

REFERENCES

[1.] Hiss RG, Lamb LE. Electrocardiographic findings in 122,043 individuals. Circulation 1962;25:947-61. [2.] Cairns JA, Connolly SJ. Nonrheumatic atrial fibrillation: risk of stroke and role of antithrombotic therapy. Circulation 1991;84:469-81. [3.] Benjamin EL, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study. JAMA 1994;271:840-4. [4.] Falk RH, Knowlton AA, Bernard SA, Gotlieb NE, Battinelli NJ. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. A randomized, double-blinded trial. Ann Intern Med 1987;106: 503-6. [5.] Platia EV, Michelson EL, Porterfield JK, Das G. Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter. Am J Cardiol 1984;63:925-9. [6.] Rawles JM, Metcalfe MJ, Jennings K. Time of occurrence, duration, and ventricular rate of paroxysmal atrial fibrillation: the effect of digoxin. Br Heart J 1990;63:225-7 [7.] Galun E, Flugelman MY, Glickson M, Eliakim M. Failure of long-term digitalization to prevent rapid ventricular response in patients with paroxysmal atrial fibrillation. Chest 1991;99:1038-40. [8.] DeCarli C, Sprouse G, LaRosa JC. Serum magnesium levels in symptomatic atrial fibrillation and their relation to rhythm control by intravenous digoxin. Am J Cardiol 1986;57:956-9. [9.] Roth A, Kaluski E, Felner S, Heller K, Laniado S. Clonidine for patients with rapid atrial fibrillation. Ann Interned 1992;116:388-90. [10.] Lowenstein SR, Gabow PA, Cramer J, Oliva PB, Ratner K. The role of alcohol in new-onset atrial fibrillation. Arch Intern Med 1983;143:1882-5. [11.] Koskinen P, Kupari M, Leinonen H. Role of alcohol in recurrences of atrial fibrillation in persons less than 65 years of age. Am J Cardiol 1990;66:954-8. [12.] Friedman HZ, Weber-Bornstein N, Deboe SF, Mancini GB. Cardiac care unit admission criteria for suspected acute myocardial infarction in new-onset atrial fibrillation. Am J Cardiol 1987;59:866-9. [13.] Shlofmitz RA, Hirsch BE, Meyer BR. New-onset atrial fibrillation: is there need for emergent hospitalization? J Gen Intern Med 1986;1:139-42. [14.] Tischler MD, Lee TH, McAndrew KA, Sax PE, Sutton MS, Lee RT. Clinical, echocardiographic and Doppler correlates of clinical instability with onset of atrial fibrillation. Am J Cardiol 1990;66:721-4. [15.] Friedman HZ, Goldberg SF, Bonema JD, Cragg DR, Hauser AM. Acute complications associated with new-onset atrial fibrillation. Am J Cardiol 1991; 67:437-9. [16.] Lipkin DP, Frenneaux M, Stewart R, Joshi J, Lowe T, McKenna WJ. Delayed improvement in exercise capacity after cardioversion of atrial fibrillation to sinus rhythm. Br Heart J 1988;59:572-7 [17.] Dittrich HC, Erickson JS, Schneiderman T, Blacky AR, Savides T, Nicod PH. Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation. Am J Cardiol 1989;63:193-7 [18.] Brodsky MA, Allen BJ, Capparrelli EV, Luckett CR, Morton R, Henry WL. Factors determining maintenance of sinus rhythm after chronic atrial fibrillation with left atrial dilatation. Am J Cardiol 1989; 63:1065-8. [19.] Sanfilippo Aj, Abascal VM, Sheehan M, Oertel LB, Harrigan P, Hughes RA, et al. Atrial enlargement as a consequence of atrial fibrillation. A prospective echocardiographic study. Circulation 1990;82:792-7 [20.] Arnold AZ, Mick MJ, Mazurek RP, Loop FD, Trohman RG. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 1992;19:851-5. [21.] Weinberg DM, Mancini J. Anticoagulation for cardioversion of atrial fibrillation. Am J Cardiol 1989;63:745-6. [22.] Manning WJ, Leeman DE, Gotch PJ, Come PC. Pulsed Doppler evaluation of atrial mechanical function after electrical cardioversion of atrial fibrillation. J Am Coll Cardiol 1989;13:617-23. [23]. O'Neill PG, Puleo PR, Bolli R, Rokey R. Return of atrial mechanical function following electrical conversion of atrial dysrhythmias. Am Heart J 1990; 120:353-9. [24.] Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781-8. [25.] Falk RH. Flecainide-induced ventricular tachycardia and fibrillation in patients treated for atrial fibrillation. Ann Intern Med 1989;111: 107-11. [26.] Disch DL, Greenberg ML, Holzberger PT, Malenka DJ, Birkmeyer JD. Managing chronic atrial fibrillation: a Markov decision analysis comparing warfarin, quinidine, and low-dose amiodarone. Ann Intern Med 1994;120:449-57 [27.] Antman EM, Beamer AD, Cantillon C, McGowan N, Friedman PL. Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged case approach with new antiarrhythmic drugs. J Am Coll Cardiol 1990;15:698-707. [28.] Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1989; 1(8631):175-9. [29.] Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990; 323:1505-11. [30.] Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527-39. [31.] Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991;18:349-55. [32.] Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, Gornick CC, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 1992;328:148-52. [33.] Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation 11 Study. Lancet 1994;343:687-91. [34.] Stroke Prevention hi Atrial Fibrillation Investigators. Warfarin compared to aspirin for prevention of arterial thromboembolism in atrial fibrillation: design and patient characteristics of the Stroke Prevention in Atrial Fibrillation 11 Study. Cerebrovasc Dis 1992;2:332-41. [35.] Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449-57 [36.] Bar-Sela S, Ehrenfeld M, Eliakim M. Arterial embolism in thyrotoxicosis with atrial fibrillation. Arch Intern Med 1981;141:1191-2. [37.] Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation 1990;82:1106-16 [published erratum appears in Circulation 1991;83:714].

COPYRIGHT 1994 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group