### Evidence Report/Technology Assessment: Number 12

# Management of New Onset Atrial Fibrillation

## Summary

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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities. 

Overview / Purpose of Evidence Report / Reporting the Evidence / Methodology / Findings / Future Research / Availability of Full Report

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## Overview

### Epidemiology

Atrial fibrillation (AF) is the most common arrhythmia physicians face in clinical practice, accounting for about one-third of hospitalizations for arrhythmia. The prevalence of AF is 0.5 percent in those 50 to 59 years old and 8.8 percent in those 80 to 89 years old, and the incidence ranges from 0.2 percent per year in men 30 to 39 years old to 2.3 percent per year in men 80 to 89 years old.

The chronic cardiac conditions most commonly associated with the development of AF are: 

- Rheumatic mitral valve disease.
- Coronary artery disease.
- Congestive heart failure.
- Hypertension.

Noncardiac etiologies, often reversible, include hyperthyroidism, hypoxic pulmonary conditions, surgery, and alcohol intoxication. No predisposing condition exists in less than 10 percent of cases; this type of AF is called "lone AF."

One classification of AF includes:

- Acute AF (onset within 48 hours).
- Paroxysmal AF (terminated spontaneously on at least one occasion).
- Persistent AF (duration greater than 48 hours and has not terminated spontaneously).
- Permanent AF (resistant to pharmacological or electrical cardioversion).

This evidence report addresses the patient who presents to a clinician for the first time with AF, whether it be persistent or paroxysmal.

The manifestations of AF can be divided into two categories: hemodynamic compromise and thromboembolic complications. Symptoms of hemodynamic compromise range from the classic complaint of irregular palpitations to the more insidious feeling of malaise. The risk of stroke is increased two- to five-fold in those with nonrheumatic AF.

### Management

In addition to treating underlying conditions, the management of AF can be divided into three areas: 

- Ventricular rate control.
- Cardioversion of AF and subsequent maintenance of sinus rhythm.
- Prevention of thromboembolism.

For rate control, clinicians generally choose among digoxin, beta-adrenergic antagonists, and/or calcium channel-blockers, without a clear consensus about which agent is the most effective.

Direct current cardioversion and numerous antiarrhythmic agents have been proposed for the cardioversion of AF. In addition, a number of pharmacological agents have been used to maintain sinus rhythm after successful cardioversion. The agents used in AF are classified by their electropharmacological actions:

- Class Ia (e.g., quinidine, procainamide, and disopyramide) and Ic (e.g., flecainide, propafenone) agents.
- Class II agents (e.g., propanolol, esmolol).
- Class III agents (e.g. amiodarone, sotalol, ibutilide, dofetilide).
- Class IV agents (e.g., verapamil, diltiazem).

Some agents have properties from different classes; particularly notable are the beta-adrenergic antagonist properties of propafenone and sotalol. The Class I and III agents are the most frequently used to convert to sinus rhythm or maintain sinus rhythm. Their use must be weighed against the risk of ventricular proarrhythmia. Again, no consensus exists regarding which strategy, electrical or pharmacological, or which agent is best.

The prevention of thromboembolic complications predominantly consists of:

- Antiplatelet therapy (e.g., aspirin, indobufen).
- Anticoagulation (e.g., heparin, coumadin).
- A combination (e.g., aspirin plus low-dose coumadin).

Most clinical experts are convinced that warfarin is the most effective agent in the majority of patients, but many clinicians remain reluctant to use warfarin because of the increased risk of bleeding, particularly in the elderly. Also, it is thought that in lower-risk patients the benefits of anticoagulation may not outweigh the risks and costs, but no absolute risk threshold has been established.

Because of safety concerns, antiarrhythmic therapy generally is started in the hospital. For economic and patient convenience reasons, some clinicians are starting certain antiarrhythmic agents in an outpatient setting for some patients. No consensus exists regarding the safety of this practice, and information is needed to determine which agents and which patients are appropriate for outpatient initiation of antiarrhythmic therapy.

Echocardiography has been proposed to aid in the management of AF in three ways:

- First, echocardiography has been proposed to stratify patients as to risk of stroke.
- Second, echocardiography has been proposed to identify patients with dilated left atria, who may be less likely to respond to cardioversion attempts.
- Third, transesophageal echocardiography has been proposed to identify patients without left-atrial thrombus, who safely could undergo acute cardioversion without the conventional 3 weeks of precardioversion anticoagulation.

There remains considerable uncertainty about the most appropriate role for echocardiography in the management of AF.

Thus, the management of patients with AF presents many options for the clinician. The initial choice of aggressive rhythm control versus appropriate rate control with treatment to prevent thromboembolism is being tested in a randomized controlled trial, but even after the results of the trial are known, questions regarding the best strategy for a given patient likely will remain.

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## Purpose of Evidence Report

This report presents the results of our assessment of the evidence on key issues in the management of AF. The target study population is those with new onset non-postoperative AF, best approximating a typical outpatient presentation. The assessment is limited to first-line strategies, excluding invasive or emerging therapies that are applied more frequently to AF refractory to first-line therapies. Relevant key questions were identified (select Identifying the Questions), a systematic review of the evidence pertinent to these questions was performed, and evidence tables of the available information were constructed. Meta-analyses and decision analyses were performed where relevant. The overall objective of this report is to synthesize the evidence that should be used to guide clinicians in their management of patients with new onset AF.

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## Reporting the Evidence

### Recruitment of Experts

We identified a core group of five clinically and/or methodologically oriented technical experts who provided extensive input throughout the project. This group included representatives from the American Academy of Family Physicians (AAFP) and a clinical expert identified through the American College of Cardiology (ACC) as well as cardiologists from Johns Hopkins medical institutions. Other technical experts aided in the identification of the relevant questions and served as peer reviewers of the evidence report. These technical experts included physicians, nurses, and representatives of professional organizations, Government agencies, health plans, and industry.

### Patient Population

The target population consisted of ambulatory adult patients with new onset AF, defined as those who present for the first time with persistent or paroxysmal AF, regardless of whether the duration of the arrhythmia is known at the time of presentation. Patients with atrial flutter were included in many of the trials on management of AF, but there were inadequate data to support separate conclusions about management of atrial flutter.

### Identifying the Questions

By giving a questionnaire to the above-mentioned technical experts, we identified the following key questions:

- 	Which patients with new onset AF should receive attempts at cardioversion and which should receive only conservative treatment with rate control and thromboembolism prophylaxis?
- 	What is the efficacy of electrical cardioversion alone compared with antiarrhythmic therapy alone compared with both together for patients with new onset AF?
- 	What are the risks and benefits of each of the antiarrhythmic agents used for conversion of AF and/or the maintenance of sinus rhythm after successful cardioversion? 
- 	What types of therapy for AF can safely be given in an outpatient setting rather than in an inpatient setting?
- 	What is the diagnostic value of tests, such as transesophageal echocardiography and transthoracic echocardiography, that can be used in the evaluation of patients with new onset AF?

In addition, two important supplementary questions, relevant to the key questions, were identified:

- 		How do various pharmacological agents differ in controlling ventricular rate in patients with AF?
- 		How does anticoagulation compare with aspirin in preventing thromboembolism in patients with AF?

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## Methodology

The primary literature source was the CENTRAL database produced by the Cochrane Collaboration's international efforts to identify controlled clinical trials. The specific search terms included "atrial fibrillation" and "atrial flutter," both as subject headings and as text words. MEDLINE also was searched to identify recent publications.

We decided to limit retrieval to randomized controlled trials in order to focus on the studies that used the strongest study design. For the questions concerning outpatient strategies (key question 4) and echocardiography (key question 5), the search strategy retrieved very few citations. It was decided for these questions to conduct additional searches, expanding retrieval to studies other than randomized controlled trials.

### Article Review Process

Overall, 521 citations were identified, and 179 articles were deemed eligible for detailed review. The following criteria were used to exclude articles from detailed review:

-  Article does not address management of AF or atrial flutter.
-  Article does not include human data.
-  Study included postoperative AF that could not be separated from data on non postoperative AF.
-  Adults are not part of the study population.
-  Study contained no original data.
-  Study lacked randomization. 
-  Study does not enable the reader to separate subjects with AF or atrial flutter from those with other arrhythmias.

Each article meeting eligibility criteria was assessed for study quality, including:

- Representativeness of the study population.
- Bias and confounding.
- Description of therapy.
- Outcomes and followup.
-  Statistical quality and interpretation.

Quantitative data were extracted on subject eligibility criteria, baseline subject characteristics that could influence outcomes (age, duration of atrial fibrillation or flutter, comorbidities, etc.), therapeutic protocols, the goal time of followup, outcomes, and adverse events. We extracted data separately for atrial fibrillation and for atrial flutter in order to address as pure a population of non-postoperative atrial fibrillation as possible.

Based on a preliminary review of the literature, the main questions identified as potentially appropriate for meta-analysis were acute pharmacological conversion, pharmacological maintenance of sinus rhythm, pharmacological heart rate control, and reduction in the rates of stroke associated with antithrombotic therapy. For the other questions that were not amenable to meta-analysis, decision analysis was used to synthesize the evidence.

### Presentation of Results and Meta-Analysis

Evidence tables were constructed for the presentation of data on pharmacological conversion, maintenance of sinus rhythm, heart rate control, and the outcomes from antithrombotic therapy. The questions with results appropriate for pooling, defined after the literature was reviewed, involved articles that met the following criteria: 

-  Had evidence from randomized clinical trials.
-  Had an adequate number of trials with qualitatively similar subjects.
-  Had an adequate number of trials that evaluated similar outcomes.

For each of the outcome measures, the treatment effect was expressed as an odds ratio; for example, the odds of converting to sinus rhythm on one drug compared with the odds of converting on another drug. In addition, we converted the pooled odds ratios into number needed to treat (NNT) data for our summary sections, in order to facilitate interpretation of the results.

A qualitative assessment of combinability was performed before a quantitative assessment of heterogeneity could be done. After review of the designs and results of the trials, we decided that the data from the trials using calcium-channel-blockers and digoxin as the comparison agents for antiarrhythmic drugs could be combined with trials that used placebo controls. Ibutilide and dofetilide were the only other pharmacological agents deemed similar enough to allow combination for pooling.

Estimates of the relative rates of the outcomes of interest were pooled using standard methods for combining odds ratios for the outcomes of conversion to sinus rhythm, maintenance of sinus rhythm, stroke, peripheral embolism, major bleeding, minor bleeding, and mortality. Studies were weighted on the basis of the precision of the estimate within each study. A fixed-effects model was used to summarize the evidence, as indicated by a screen for quantitative heterogeneity. In two instances with respect to the conversion data—propafenone versus control treatment and amiodarone versus control treatment—a random-effects model was used because of some quantitative heterogeneity of the data. The impact of the baseline characteristics of the subjects within each study on the aggregate study outcomes was evaluated. Although only large subgroup effects could be detected because of the small numbers of studies, we thought it was important to explore certain clinically relevant subgroups.

Realizing it is difficult to categorize the strength of evidence, we felt it was important to facilitate interpretation of the odds ratio (OR). The concept of "strength of evidence" depends on the estimated magnitude of effect, the precision of that estimate, and our confidence that the true effect is different from zero. Quantitatively, all of these dimensions are captured by the point estimate and confidence interval (CI), but it may be difficult to interpret results presented only in that fashion. Therefore, we provided descriptors of the strength of evidence. For the evidence on conversion and maintenance of sinus rhythm, an OR greater than 1.0 represents a higher odds of conversion or maintenance of sinus rhythm compared with the comparison group. For the evidence on anticoagulation and antiplatelet agents, an OR less than 1.0 represents a lower odds of adverse events such as stroke and bleeding compared with the comparison group.

We chose the following categorization of strength of evidence by noting the placement of the point estimate and the width of the CI surrounding it:

*Conversion and Maintenance of Sinus Rhythm*:

- 	Strong evidence of efficacy: OR > 1.0, 99 percent CI does not include 1.0 (p < 0.01).
- 	Moderate evidence of efficacy: OR > 1.0, 95 percent CI does not include 1.0, but 99 percent CI includes 1.0 (0.01 < p < 0.05).
- 	Suggestive evidence of efficacy: 95 percent CI includes 1.0 in the lower tail (0.05 < p < 0.2 to 0.3) and the OR is in a clinically meaningful range.
- 	Inconclusive evidence of efficacy: 95 percent CI widely distributed around 1.0.
- 	Strong evidence of lack of efficacy: OR near 1.0, 95 percent CI is narrow.	

When the point estimate was less than 1.0, we termed this negative efficacy and used the same categorization of strong, moderate, and suggestive evidence based on the CI.

*Anticoagulation and Antiplatelet Agents*:

- 	Strong evidence of efficacy: OR < 1.0, 99 percent CI does not include 1.0 (p < 0.01).
- 	Moderate evidence of efficacy: OR < 1.0, 95 percent CI does not include 1.0, but 99 percent CI includes 1.0 (0.01 < p < 0.05).
- 	Suggestive evidence of efficacy: 95 percent CI includes 1.0 in the upper tail (0.05 < p < 0.2 to 0.3) and the OR is in a clinically meaningful range.
- 	Inconclusive evidence of efficacy: 95 percent CI is widely distributed around 1.0.
- 	Strong evidence of lack of efficacy: 95 percent CI symmetrically and narrowly distributed around 1.0.

When the point estimate was greater than 1.0, we termed this negative efficacy and used the same categorization of strong, moderate, and suggestive evidence based on the CI.

There were some situations in which the above categorizations did not completely capture some element of the results that was important for interpretation, particularly in cases with large point estimates and/or very wide confidence intervals. In those instances, we added additional descriptive text.

### Decision Analysis

A Monte Carlo multistate transition model was constructed to evaluate the cost effectiveness questions not directly or fully addressed in the clinical trial literature.

First, to address the question of what combination of electrical or pharmacological intervention is most cost effective for cardioversion and subsequent maintenance of sinus rhythm (key questions 2 and 3), 17 strategies were evaluated.

- (A)	Electrical cardioversion without subsequent pharmacological therapy.
- (B-G)	Pharmacological conversion using either quinidine, flecainide, propafenone, amiodarone, sotalol, or ibutilide without subsequent pharmacological therapy.
- (H-L)	Pharmacological conversion with continued therapy using one of the following: quinidine, flecainide, propafenone, amiodarone, or sotalol (ibutilide cannot be used for continued therapy).
- (M-Q)	Electrical cardioversion with subsequent maintenance of sinus rhythm using one of the five agents listed above.

Second, to address the question of what antithrombotic therapy is most cost effective for the prevention of stroke (supplementary question 2), strategies employing aspirin and warfarin were evaluated.

Third, by comparing the most cost-effective strategies from each of the above two analyses, the overall question of whether to attempt cardioversion or to treat conservatively with antithrombotic therapy (key question 1) was addressed.

Fourth, the implications of the costs of inpatient versus outpatient initiation of antiarrhythmic therapy on the cost-effectiveness of the strategies for cardioversion and subsequent maintenance of sinus rhythm (key question 4) were evaluated.

Finally, the question regarding the use of echocardiography to guide antithrombotic therapy (key question 5) was addressed. Strategies employing transesophageal echocardiography or transthoracic echocardiography to guide decisions about antithrombotic therapy were compared with the strategy employing either aspirin in all patients or warfarin in all patients.

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## Findings

### Literature Search

Questions regarding pharmacological conversion of AF and maintenance of sinus rhythm, pharmacological rate control, and antithrombotic therapy were addressed directly in the clinical trial literature. Other areas were addressed only indirectly in this body of literature and needed supplementation from observational studies. Two large randomized clinical trials are under way that will address overall rate versus rhythm control and value of transesophageal echocardiography in guiding timing for acute cardioversion.

### Efficacy of Antiarrhythmic Agents in Management of Non-Postoperative AF (Key Questions 1-3)

This review of the literature identified 46 randomized clinical trials on acute cardioversion of AF that included 18 antiarrhythmic agents, listed according to the Vaughan-Williams classification system.

- 	Class Ia: Quinidine, procainamide, disopyramide.
- 	Class Ic: Flecainide, propafenone.
- 	Class II: Beta-blockers (timolol, practolol).
- 	Class III: Amiodarone, sotalol, ibutilide, dofetilide.
- 	Class IV: Verapamil, diltiazem.
- 	Class V: Digoxin.
- 	Miscellaneous: Cibenzoline, pirmenol, pilsicainide, magnesium.

This review of the literature identified 29 randomized clinical trials on maintenance of sinus rhythm that included 10 antiarrhythmic agents:

- 	Class Ia: Quinidine, disopyramide.
- 	Class Ic: Flecainide, propafenone.
- 	Class III: Amiodarone, sotalol, N-acetylprocainamide.
- 	Class IV: Verapamil.
- 	Miscellaneous: Cibenzoline, bidisomide.

The overall quality scores ranged from a low of 36 percent to a high of 95 percent. It is of note, however, that only nine studies had an overall quality score less than 50 percent. The studies had the largest variability in terms of representativeness of the population, with a range of scores from 0 to 100 percent. All of the other four domains of quality also had considerable variation in scores, with the following ranges: 

- Bias and confounding, 17 to 100 percent.
- Therapy description, 25 to 100 percent.
- Outcomes assessment, 25 to 90 percent.
- Statistical analysis, 0 to 100 percent.

Our review of the literature supported the combination of placebo, verapamil, diltiazem, and digoxin into a control treatment group. The bulk of the evidence reported on comparisons of a given antiarrhythmic agent with one of these control groups.

The evidence regarding adverse events, including ventricular arrhythmias, was reported inconsistently and sporadically, limiting its usefulness in this review in both quantitative and qualitative terms.

The evidence on clinical predictors of success in pharmacological conversion was too sparse and disparate to summarize meaningfully.

### Pharmacological conversion of AF

**Strong evidence of efficacy (compared with control treatment).** The antiarrhythmic agents with the strongest evidence of efficacy and largest treatment effect sizes for conversion of AF, compared with control treatment, were flecainide (OR 24.7, CI 9.0-68.3) and ibutilide/dofetilide (OR 29.1, CI 9.8-86.1). Assuming a control treatment cardioversion rate of 30 percent and using the upper and lower 95 percent confidence limits on these odds ratios, the estimated number of subjects needed to be treated (NNT) in order to see a benefit relative to control treatment ranged from 1.5 to 2.0 for either flecainide or ibutilide/dofetilide.

Strong evidence of efficacy compared with control treatment also existed for propafenone (OR 4.6, CI 2.6-8.2), with a fairly large treatment effect size. Again assuming a control treatment conversion rate of 30 percent and using the upper and lower 95 percent confidence limits on this odds ratio, the estimated NNT in order to see a benefit relative to control treatment ranged from 2.0 to 4.5 for propafenone.

We should note here that the NNT is sensitive to the baseline assumption of the control treatment cardioversion rate. For example, if we varied the control treatment cardioversion rate from 5 percent to 75 percent for propafenone, the NNT ranges became 4.0 to 14.3 for a 5 percent conversion rate and 4.7 to 7.5 for a 75 percent conversion rate.

**Moderate evidence of efficacy (compared with control treatment).** There was moderate evidence of efficacy with a modest treatment effect size for quinidine compared with control treatment for cardioversion of AF (OR 2.9, CI 1.2-7.0). Assuming a control treatment cardioversion rate of 30 percent and using the 95 percent confidence limits, the range of number of subjects needed to be treated with quinidine in order to see a benefit relative to control treatment is 2.0-25.0.

**Suggestive evidence of efficacy (compared with control treatment).** Disopyramide (OR 7.0, CI 0.3-153) and amiodarone (OR 5.7, CI 1.0-33.4) had suggestive evidence of benefit for acute conversion of AF relative to control treatment. The comparison of amiodarone with control treatment, however, was problematic because of the substantial qualitative and quantitative heterogeneity between the combined studies.

**Suggestive evidence of negative efficacy (compared with control treatment).** The evidence was suggestive of negative efficacy of sotalol (OR 0.4, CI 0.0-3.0) compared with control treatment for acute cardioversion of AF.

**Minimal evidence.** Minimal evidence existed for agents in Classes II, IV, and V, and in the miscellaneous category.

### Pharmacological Maintenance of Sinus Rhythm

**Strong evidence of efficacy (compared with control treatment).** All of the following antiarrhythmic agents had strong evidence of efficacy and fairly large treatment effect sizes for maintenance of sinus rhythm in AF: quinidine (OR 4.1, CI 2.5-6.7), disopyramide (OR 3.4, CI 1.6-7.1), flecainide (OR 3.1, CI 1.5-6.2), propafenone (OR 3.7, CI 2.4-5.7), and sotalol (OR 7.1, CI 3.8-13.4). Our review did not support any definitive ranking of these five agents for their efficacy in maintaining sinus rhythm. Using an assumption of 30 percent recurrence of AF by 6 months in the control treatment group and the upper and lower 95 percent confidence limits of these odds ratios, the NNT range for each agent in order to see a benefit relative to control treatment is as follows: quinidine 2.3-4.6; disopyramide 2.2-9.4; flecainide 2.3-10.9; propafenone 2.4-4.8; and sotalol 1.8-3.1.

**Potentially strong evidence of efficacy (compared with control treatment).** There was a paucity of evidence on use of amiodarone for maintenance of sinus rhythm after cardioversion of AF. One trial, presenting only interim results, had moderate evidence of amiodarone efficacy relative to disopyramide. Because disopyramide had strong evidence of efficacy relative to control treatment, we chose to classify the evidence on amiodarone as "potentially strong evidence" relative to control treatment. Notably, however, we identified no trials of amiodarone compared with control treatment for maintenance of sinus rhythm.

Clinical trials now in progress will help address the paucity of data on amiodarone for maintenance of sinus rhythm.

**Minimal evidence.** Minimal evidence existed for N-acetylprocainamide and agents in Class IV and the miscellaneous category.

**From the decision analysis.** One attempt at electrical cardioversion with subsequent pharmacological maintenance therapy is cost effective compared with conservative antithrombotic therapy alone for all patients 55 years old or older, regardless of risk factors.

### Efficacy of Drugs for Achieving Ventricular Rate Control of Patients with AF (Supplementary Question 1)

Overall, 45 trials were identified that evaluated 17 agents. The design and outcomes of these trials were too disparate for meta-analysis. Generally, the studies were of high quality in their description of the outcomes and for having objective measures of the outcomes. The studies were weaker in their description of the study groups; it was not always possible to determine if the groups were similar.

Compared with placebo or digoxin, the calcium-channel-blockers diltiazem and verapamil were effective in reducing the heart rate at rest and during exercise in patients with AF.

Compared with placebo or digoxin, beta-blockers were effective in reducing the heart rate during exercise in patients with AF. However, exercise tolerance was decreased on beta-blockers in a number of the studies. The effect of beta-blockers on resting heart rate was inconsistent, with only about half of the studies demonstrating better control with beta-blockers than placebo.

The evidence was not convincing for the use of digoxin, particularly during exercise.

### Efficacy of Anticoagulants and Antiplatelet Agents in Management of AF and Meta-Analysis of Results (Supplementary Question 2)

**Antithrombotic therapy.** For antithrombotic therapy, 11 trials were identified that evaluated 4 medications.

Strong evidence for the prevention of stroke existed for use of warfarin (OR 0.30, CI 0.19-0.48) compared with placebo. However, the evidence was suggestive of a higher bleeding rate on warfarin (OR 1.90, CI 0.89-4.04) than placebo. For every 1,000 patients with AF who are treated with warfarin for 1 year, 30 strokes are prevented at the expense of 6 major bleeds.

The evidence for efficacy in preventing stroke was moderately strong for aspirin (OR 0.65; CI 0.43-0.99) compared with placebo. The evidence for an increased odds of major bleeding associated with aspirin (OR 0.81, CI 0.37-1.77) compared with placebo was inconclusive. For every 1,000 patients with AF who are treated with aspirin for 1 year, 12.5 strokes are prevented.

The evidence from trials directly comparing warfarin and aspirin did not permit strong conclusions.

The evidence was inconclusive about the use of a combination of low-dose warfarin with aspirin and about the use of low molecular weight heparin or induprofen for stroke prevention.

**From the decision analysis.** Our decision analysis estimated that for patients at low risk of stroke (~1 percent/year), aspirin is the most cost-effective therapy. For patients with a high risk of stroke (~10 percent/year), warfarin is projected to be the most cost-effective strategy. For those with an intermediate risk of ischemic stroke (~3-6 percent/year), aspirin therapy is estimated to be the most cost effective if quality of life is assumed to be decreased by taking warfarin. If no decrease in quality of life is assumed, warfarin is estimated to be the most cost-effective strategy for the intermediate-risk groups.

### Outpatient Initiation of Antiarrhythmic Therapy (Key Question 4)

Our comprehensive literature search did not identify any randomized controlled clinical trials that addressed directly the question of what types of therapy for AF can safely be given in an outpatient setting (key question 4).

Based on the decision analysis, if antiarrhythmic therapy can be started safely as an outpatient, the cost-effectiveness of an attempt of electrical cardioversion with pharmacological maintenance therapy is improved considerably. However, more research is needed in this area to determine the safety of this practice.

### Echocardiography (Key Question 5)

From our comprehensive literature search of clinical trials, no completed trials were identified that directly addressed the clinical utility of echocardiography in the management of AF (key question 5).

Of the 46 studies of acute cardioversion identified in our comprehensive search of clinical trials, only 9 gave information relating left-atrial diameter from echocardiography to success of cardioversion. Although the results were not consistent, there was a suggestion of an inverse association between left-atrial diameter and successful cardioversion.

Based on the decision analysis, transthoracic echocardiography is projected to be a cost-effective test for guiding decisions about the choice of antithrombotic treatment in most patients without risk factors for thromboembolism. Transesophageal echocardiography is projected to be a cost-effective test for guiding decisions about the choice of antithrombotic treatment in patients having risk factors for thromboembolism.

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## Future Research

Two ongoing clinical trials are addressing two of the key questions. One is addressing the decision about aggressive rhythm control versus conservative rate control with antithrombotic therapy. The other is evaluating the use of transesophageal echocardiography in guiding the timing of acute cardioversion of AF.

Future research should include randomized controlled trials and other types of studies:

- 	Incorporating assessment of the quality of life of patients with AF.
- 	Directly comparing the efficacy and safety of multiple active antiarrhythmic agents, particularly amiodarone, and their effect in different patient subgroups, such as those with coronary artery disease.
- 	Developing and/or incorporating strategies for safe outpatient initiation of antiarrhythmic therapy.
- 	Comparing warfarin, aspirin, and other antithrombotic agents in moderate-risk and low-risk populations.
- 	Addressing the role of transthoracic and transesophageal echocardiography in identifying patient subgroups for different management options.

Many of these recommended research priorities, and specifically the second one, are beginning to be addressed in trials now being conducted.

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## Availability of Full Report

The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Researchand Quality by the Johns Hopkins University, Baltimore, MD, under contract  No. 290-97-0006. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment Number 12, *Management of New Onset Atrial Fibrillation* (AHRQ Publication  No. 00-E007).

 The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a zipped file.

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*AHRQ Publication  No. 00-E006Current as of May 2000*

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**Internet Citation:**

*Management of New Onset Atrial Fibrillation*. Summary, Evidence Report/Technology Assessment: Number 12. AHRQ Publication  No. 00-E006, May 2000. Agency for Healthcare Researchand Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/atrialsum.htm

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