Skip Navigation
Department of Health and Human Services www.hhs.gov
  • Home
  • Search for Research Summaries, Reviews, and Reports
 
 

EHC Component

  • EPC Project

Full Report

Related Products for this Topic

Save this page in Facebook.com  Save this page in Myspace.com  Save this page in Twitter.com  Save this page on your Google Home Page  Save this page in Windows Live
Save this page in Yahoo  Save this page in Ask.com  Stumble this page.  Save this page in del.ico.us  Digg this page. 

E-mail E-mail   Print Print

Add to My Collections



Research Protocol – Jan. 27, 2012

Treatment of Atrial Fibrillation

Formats

On May 22, 2011, several amendments were made to this protocol. To view these amendments, please see the section titled “Summary of Protocol Amendments.”

Table of Contents

Background and Objectives for the Systematic Review

Definition and Impact of Atrial Fibrillation

Atrial fibrillation (AF) is a major public health problem in the United States. It is estimated that more than 2.3 million Americans have paroxysmal or persistent AF.1 The prevalence of AF increases with age and approaches 8 percent in patients older than 80 years of age.2 As such, AF is the most common sustained arrhythmia seen in clinical practice. 

The impact of AF is compounded by its known association with significant mortality, morbidity, and health care costs. Not only is the risk of death in patients with AF twice that of patients without AF, but AF can result in myocardial ischemia or even infarction, heart failure exacerbation, and tachycardia-induced cardiomyopathy if the ventricular rate is not well-controlled.3-6 In some patients, AF can severely depreciate quality of life by causing shortness of breath, intractable fatigue, and near-syncope.7-10 However, the most dreaded complication of AF is thromboembolism, especially stroke. The risk of stroke in patients with nonrheumatic AF is 5 percent per year, and this risk approaches 7 percent per year in patients with heart failure.11 Importantly, when ischemic stroke occurs in patients with AF, it is either fatal or of moderate to high severity in most patients.12 The management of AF and its complications is responsible for almost $16 billion in additional costs to the U.S. health care system each year.13

This substantial public health impact of AF in the United States led the Institute of Medicine to designate AF as one of the top priority areas for comparative effectiveness research. Specifically, the Institute called upon researchers to compare the effectiveness of treatment strategies for AF, including surgery, catheter ablation, and pharmacological treatment.14

Management of AF

Management of AF involves three distinct areas, namely rate control, rhythm control, and prevention of thromboembolic events. This project will focus on the first two areas. A second comparative effectiveness review focusing on the prevention of thromboembolic events is being performed in parallel.

Rate Control

Whether or not a rhythm-control strategy is adopted, adequate rate control should be achieved in all patients with AF to prevent myocardial infarction (if significant coronary artery disease is present), exacerbation of heart failure, and tachycardia-induced cardiomyopathy and to alleviate symptoms. Thus, the 2006 Guidelines for the Management of Patients with Atrial Fibrillation—prepared jointly by the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC)—highlight the need for adequate rate control in patients with AF and designate measurement of the heart rate at rest and control of the rate with pharmacological agents (either a beta-blocker or a nonhydropyridine calcium channel blocker in most patients with AF) as a Class I recommendation.13 However, since the development of the ACC/AHA/ESC Guidelines many additional studies have been published on the comparative safety and effectiveness of the different available medications used for ventricular rate control in clinical practice. Thus, an updated review of published studies and synthesis of available data are very timely. 

If pharmacological therapy is insufficient or associated with side effects, the 2006 ACC/AHA/ESC Guidelines recommend ablation of the atrioventricular node (AVN) in conjunction with permanent pacemaker implantation to control heart rate.13 This recommendation is based on several studies that showed effective heart rate control and improvement in symptoms with AVN ablation and permanent pacemaker implantation in selected patients with AF.15-18 However, the most recent systematic review was published more than a decade ago. It is important to synthesize the evidence that has been published since then to better define the role of this procedure in contemporary clinical practice and specific subpopulations where it might be more or less effective and clinically needed.

The 2011 Focused Update on the Management of Patients with Atrial Fibrillation—by the American College of Cardiology Foundation (ACCF), the AHA, and the Heart Rhythm Society (HRS)—addressed the issue of strict versus lenient rate control in patients with AF.19 This update was prompted by the results of the Rate Control Efficacy in Permanent Atrial Fibrillation-II (RACE-II) trial.20 This trial enrolled 614 patients with permanent AF and randomized them to strict rate control (resting heart rate <80 beats per minute [bpm], heart rate <110 bpm during moderate exercise) and lenient rate control (resting heart rate <110 bpm). The primary end point was a composite of death from cardiovascular causes, hospitalization for heart failure, stroke, systemic embolism, bleeding, and life-threatening arrhythmias. Although this trial showed that lenient rate control is as effective as strict rate control and is easier to achieve, it was not adequately powered to permit definitive conclusions.20 Thus, it is important to examine all available evidence on strict versus lenient rate control to define the comparative safety and effectiveness of these strategies that could help inform decisions made in clinical practice.

Rhythm Control

If patients with AF continue to have significant symptoms despite adequate rate control, then a rhythm-control strategy (either pharmacological or electrical) should be pursued. In addition, when AF affects younger patients (<65 years of age), a rhythm-control strategy is often considered reasonable even in the absence of substantial symptoms. For pharmacological cardioversion of AF, the 2006 ACC/AHA/ESC Guidelines recommend flecainide, dofetilide, propafenone, and ibutilide as Class I recommendations and amiodarone as a Class IIa recommendation.13 To enhance direct-current cardioversion, the 2006 ACC/AHA/ESC Guidelines recommend pretreatment with amiodarone, flecainide, ibutilide, propafenone, or sotalol. For maintenance of sinus rhythm after cardioversion, the 2006 ACC/AHA/ESC Guidelines list different antiarrhythmic medications for different clinical settings. The 2011 ACCF/AHA/HRS Focused Update builds upon the recommendations in the 2006 ACC/AHA/ESC Guidelines using published data on new antiarrhythmic medications. Guideline recommendations are depicted in Figure 1;19 however, which of these medications is best for which patients is uncertain. Thus, a review of existing evidence and a summary of evidence gaps are urgently needed on the comparative safety and effectiveness of available antiarrhythmic agents for conversion of AF to sinus rhythm, for ensuring successful electrical cardioversion, and for maintaining sinus rhythm after successful conversion of AF to sinus rhythm.

Figure 1. Current guideline recommendations for maintenance of sinus rhythm

Figure 1 summarizes current (2011) guideline recommendations on the maintenance of sinus rhythm in patients with atrial fibrillation from the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Treatment algorithms are depicted for four categories of atrial fibrillation patients: those with no (or minimal) heart disease, those with hypertension, those with coronary artery disease, and those with heart failure. For patients with no (or minimal) heart disease, initial treatment options include dronedarone, flecainide, propafenone, and sotalol. Secondary treatment options include amiodarone and dofetilide (drug therapies) or catheter ablation. For patients with hypertension, the figure indicates that treatment options depend on whether or not the patient also has substantial left ventricular hypertrophy. If “no”, then treatment options are the same as for patient with no (or minimal) heart disease: that is, initial treatment options include dronedarone, flecainide, propafenone, and sotalol, and secondary treatment options include amiodarone and dofetilide (drug therapies) or catheter ablation. If “yes” (substantial left ventricular hypertrophy), then initial treatment is with amiodarone, followed by catheter ablation, if necessary. For patients with coronary artery disease, initial treatment options include dofetilide, dronedarone, and sotalol, and secondary treatment options are amiodarone or catheter ablation. Finally, for patients with heart failure, initial treatment options are amiodarone and dofetilide, followed by catheter ablation, if necessary.

Abbreviations: LVH = left ventricular hypertrophy

In addition to pharmacological and direct current cardioversion, a number of surgical options are used for rhythm control. Catheter ablation for the treatment of AF has evolved rapidly from a highly experimental procedure to its current status as a commonly performed procedure now established as a clinically useful treatment option for symptomatic patients in whom medications are not effective or not tolerated.13,19,21

Many studies have provided information on the safety and efficacy of catheter ablation of AF. These studies vary from small and large nonrandomized, single-center studies to prospective randomized multicenter clinical trials. The strongest evidence supporting the efficacy of catheter ablation for AF was generated by 8 randomized controlled trials (RCTs) that enrolled a total of 930 patients.22-29 Four of these trials22,25,26,29 enrolled patients with paroxysmal or persistent AF, three enrolled only patients with paroxysmal AF,24,27,28 and one enrolled only patients with persistent AF.23 Seven trials22,24-29 compared catheter ablation with antiarrhythmic medication(s), and one trial randomized patients to catheter ablation or cardioversion, followed by 3 months of amiodarone therapy in both arms.23 Catheter ablation was associated with a significant improvement in freedom from AF in all trials.22-29 However, these studies have several limitations. The relatively small number of patients included in each trial makes definitive conclusions about the safety and efficacy of pulmonary vein isolation difficult and does not permit meaningful analyses of key subgroups of patients (e.g., older patients, patients with heart failure). In addition, two of these trials were single-center studies,22,23 and the followup period in all trials was limited to 12 months. None of the trials provided data on hard end points like mortality and stroke. These limitations underscore the importance of synthesizing the evidence on this procedure not only by pooling data from these studies, but also by including the results of other studies, such as prospective cohort studies and comparative effectiveness research projects using national registries.

Several other procedures have been investigated in the treatment of AF. One such procedure is the surgical Maze procedure, which appears to confer some benefit to selected patients with AF.30 Another procedure that may be of benefit is implantation of a cardiac resynchronization therapy (CRT) device. In one study, 1 in every 10 patients with heart failure and permanent AF converted to sinus rhythm after receiving a CRT device. Predictors of conversion to sinus rhythm included baseline end-diastolic diameter ≤ 65 mm, CRT-paced QRS ≤ 150 ms, left atrial diameter ≤ 5 cm, and AVN ablation.31 Several other studies have suggested that CRT may be beneficial in restoring sinus rhythm in patients with persistent or permanent AF; however, at least one large substudy from the CArdiac REsynchronisation in Heart Failure (CARE-HF) trial showed no reduction in the incidence of AF with CRT.32-35 It is important to review published data on these procedures to better define their role in contemporary clinical practice.

Finally, a few small observational studies have suggested that autonomic ganglionic plexi ablation or denervation may play a role in treating AF, but these findings have not been confirmed by RCTs, and uncertainty exists as to the comparative safety and effectiveness of these strategies.36-39

In selecting treatment modalities most likely to produce successful results in rhythm control, few diagnostic studies or risk models exist to guide practicing clinicians in predicting response to available therapies in individual patients. Previous studies have examined the role of clinical factors (such as age, existence of congestive heart failure or left ventricular dysfunction, diabetes, etc.), duration of AF, and/or prior attempts at cardioversion in predicting response to therapies, especially response to electrical and pharmacological cardioversion.40,41 Additionally, imaging parameters—particularly echocardiographic criteria such as left ventricular wall thickness, left atrial dimension, left atrial appendage flow, and left ventricular function—have been examined as potential risk variables in the prediction of successful rhythm-control strategies.42-44 However, these clinical and imaging parameters have not been systematically reviewed to determine their role or potential evidence gaps for their use in routine clinical practice. Data are also lacking on clinical and echocardiographic predictors of response to catheter ablation of AF. Data synthesis on this topic would be of great benefit to practicing physicians in helping them select the best patients for each available therapeutic modality.

Rate Control Versus Rhythm Control

Several uncertainties around AF management remain. Specifically, the comparative risks and benefits of rate-control versus rhythm-control strategies for patients with AF remain uncertain. It is still not known if maintaining patients with AF in sinus rhythm provides any survival benefit. We also do not know if different types of AF can affect outcomes differently, or how different therapies affect different types of AF.

Rate-control versus rhythm-control strategies for patients with AF have been evaluated in previous studies. Several RCTs showed no significant difference in the outcomes of patients treated with a rate-control strategy versus a rhythm-control strategy with an antiarrhythmic medication even in the presence of heart failure.45-50 In fact, one pivotal trial—the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial—showed a trend toward a higher risk of death with a rhythm-control strategy than with a rate-control strategy (26.7 percent vs. 25.9 percent, p = 0.08).46 The AFFRIM trial enrolled patients who were elderly and had several comorbidities. Most patients, however, had a normal ejection fraction. The findings of this important study suggest that in patients with AF and comorbidities (including advanced age), using rate control as an initial strategy with adequate anticoagulation therapy might be enough to prevent death from any cause.

Despite these studies, several uncertainties around AF management remain, and comparative safety and effectiveness analyses of these available management strategies for patients with AF are needed. Thus, a review of the available data (from various study designs) will not only address these uncertainties, but it will define gaps in knowledge and identify important future research needs.

Policy Issues

By summarizing data that support improved management of AF, we hope to enhance patient-centered outcomes and reduce health care utilization and costs. Thus, our findings will have direct implications for improved patient care and for the allocation of Medicare and other health care resources. This project will benefit patients, providers, payers, and policymakers. Patients will benefit from more robust data on the comparative safety and effectiveness of different therapeutic strategies for AF. Providers will benefit by gaining a better understanding of which patients benefit the most from maintenance of sinus rhythm and of barriers to implementation of practice guidelines and current treatment strategies. Policymakers will be able to design and implement programs to make better use of scarce health care resources while improving the health status of adult patients with AF.

The Key Questions

The draft Key Questions (KQs) that were developed during Topic Refinement were available for public comment from September 27, 2011, to October 25, 2011. The comments received led to the inclusion of additional subgroups of interest; clarification that we will be exploring the comparative safety and effectiveness of specific pharmacological agents in comparison to other such agents; and confirming that our emphasis is on patient-centered outcomes. There were no other significant changes to our KQs or proposed methods.

Our first three KQs focus on rate-control therapies. Specifically:

KQ 1: What are the comparative safety and effectiveness of pharmacological agents used for ventricular rate control in patients with AF? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest?

KQ 2: What are the comparative safety and effectiveness of a strict rate-control strategy versus a more lenient rate-control strategy in patients with AF? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest?

KQ 3: What are the comparative safety and effectiveness of newer procedural and other nonpharmacological rate-control therapies compared with pharmacological agents in patients with AF who have failed initial pharmacotherapy? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest?

Our next three KQs focus specifically on rhythm-control therapies:

KQ 4: What are the comparative safety and effectiveness of available antiarrhythmic agents and electrical cardioversion for conversion of AF to sinus rhythm? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest?

KQ 5: What are the comparative safety and effectiveness of newer procedural rhythm-control therapies, other nonpharmacological rhythm-control therapies, and pharmacological agents (either separately or in combination with each other) for maintenance of sinus rhythm in patients with AF? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest?

KQ 6: What are the comparative diagnostic accuracy, diagnostic thinking, therapeutic, and patient outcome efficacy of echocardiographic studies and other clinical parameters for predicting successful conversion, successful ablation, successful maintenance of sinus rhythm, and improved outcomes in patients with AF?

Our final KQ seeks to evaluate the comparison of the available rate- and rhythm-control therapies.

KQ 7: What are the comparative safety and effectiveness of rhythm-control therapies compared to rate-control therapies in patients with AF? Does the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest?

PICOTS (Populations, Interventions, Comparators, Outcomes, Timing, and Settings)

  • Populations:
    • Adults (age > 18 years) with AF (includes atrial flutter):
      • Including paroxysmal AF (recurrent episodes that self-terminate in less than 7 days), persistent AF (recurrent episodes that last more than 7 days), and permanent AF (an ongoing long-term episode)
      • Excluding patients with known reversible causes of AF (including but not limited to postoperative, postmyocardial infarction, hyperthyroidism)
    • Specific populations of interest include (KQs 1–7):
      • Patients stratified by age (≤40, 41–64, 65–74, 75–84, 85+)
      • Patients with different types of AF (paroxysmal, persistent, or permanent)
      • Patients with specific comorbidities (heart failure, coronary artery disease, kidney disease, hypertrophic cardiomyopathy, thyroid disease, or pulmonary disease)
      • Patients who have previously failed a previous rate-control (KQ 3) or rhythm-control (KQ 5) pharmacological therapeutic strategy
      • Women
      • Patients with an enlarged left atrium
      • Patients at high risk for stroke and bleeding events (e.g., patients with diabetes, heart failure, and hypertension)
      • Patients stratified by race/ethnicity
  • Interventions:
    • Pharmacological agents for rate control (KQs 1, 2, 3, and 7):
      • Beta-blockers (e.g., acebutolol, atenolol, bisoprolol, carvedilol, esmolol [acute rate lowering only], metoprolol, nadalol, nebivolol, timolol)
      • Calcium channel blockers (verapamil, diltiazem)
      • Other (digoxin, amiodarone, dronedarone)
    • Procedures for rate control (KQs 3 and 7)
      • AVN ablation and permanent pacemaker implantation
    • Pharmacological agents for rhythm control (KQs 4, 5, and 7):
      • Amiodarone
      • Disopyramide
      • Dofetilide
      • Dronedarone
      • Flecainide
      • Ibutilide (acute conversion only)
      • Propafenone
      • Sotalol
    • Procedures for rhythm control (KQs 5 and 7)
      • Electrical cardioversion
      • AF ablation by pulmonary vein isolation
      • Open surgical procedures
      • Minimally invasive procedures
      • Transcatheter procedures
      • Surgical Maze procedure
      • Cardiac resynchronization therapy
    • Echocardiography to predict successful treatment of AF (conversion, ablation, maintenance of sinus rhythm) (KQ 6)
  • Comparators:
    • KQ 1: Other rate-control pharmacological agents
    • KQ 2: Other strict/lenient rate-control strategies
    • KQ 3: Other procedural, nonpharmacological, and other specific individual pharmacological rate-control therapies
    • KQ 4: Other antiarrhythmic agents
    • KQ 5: Other procedural, nonpharmacological, and other specific pharmacological rhythm-control therapies
    • KQ 6: Other clinical parameters for predicting successful conversion, successful ablation, successful maintenance of sinus rhythm, and improved outcomes in patients with AF (e.g., duration of AF, heart failure, coronary artery disease)
    • KQ 7: Other rhythm-control or rate-control therapies
  • Patient-Centered Outcome Measures:
    • Intermediate outcomes:
      • Restoration of sinus rhythm (conversion)
      • Maintenance of sinus rhythm
      • Recurrence of AF at 12 months
      • Development of cardiomyopathy
      • Diagnostic accuracy efficacy, diagnostic thinking efficacy, therapeutic efficacy, and patient outcome efficacy of echocardiographic studies (KQ 6 only)
    • Final outcomes:
      • Mortality (all-cause, cardiac)
      • Myocardial infarction
      • Cardiovascular hospitalizations
      • Heart failure symptoms
      • Control of AF symptoms (e.g., palpitations, exercise capacity)
      • Quality of life
      • Functional status
      • Stroke and other embolic events
      • Bleeding events
    • Adverse effects of intervention(s):
      • Adverse effects from drug therapies (e.g., hypotension, hypothyroidism and hyperthyroidism, arrhythmias [bradyarrhythmias, tachyarrhythmias, or proarrhythmias], allergic reactions, hepatotoxicity, neurotoxicity, pulmonary toxicity, ophthalmologic toxicity, dermatologic toxicity)
      • Procedural complications (e.g., pulmonary vein stenosis, left atrial esophageal fistula, and phrenic nerve palsy)
  • Timing:
    • Short term (e.g., restoration of sinus rhythm and control of symptoms)
    • Long term (e.g., mortality and maintenance of sinus rhythm)
  • Settings:
    • All settings

Analytic Framework

Figure 2. Provisional analytic framework for the treatment of atrial fibrillation

Figure 2 is an analytic framework that depicts the key questions within the context of the PICO (populations, interventions, comparators, and outcomes) described elsewhere in this document. The patient population of interest is adults with atrial fibrillation. Interventions of interest are procedural and nonpharmacological therapies for rate control (key questions 3 and 7), pharmacological therapies for rate control (key questions 1, 2, 3, and 7), pharmacological therapies for rhythm control (key questions 4, 5, and 7), electrical cardioversion (key questions 4, 5, and 7), and procedural and nonpharmacological therapies for rhythm control (key questions 5 and 7). Strict versus more lenient pharmacological therapies for rate control are considered in a separate question (key question 2). Intermediate outcome measures of interest are restoration of sinus rhythm, maintenance of sinus rhythm, development of cardiomyopathy, and recurrence of atrial fibrillation at 12 months. Final outcomes of interest are mortality (all-cause and cardiac), myocardial infarction, cardiovascular hospitalizations, heart failure symptoms, control of atrial fibrillation symptoms (e.g., palpitations, exercise capacity), quality of life, functional status, stroke and other embolic events, and bleeding events. Adverse events associated with pharmacological treatment include hypotension, hypo/hyperthyroidism, arrhythmias, allergic reactions, hepatotoxicity, neurotoxicity, pulmonary toxicity, ophthalmological toxicity, and dermatological toxicity. Procedural complications include pulmonary vein stenosis, left atrial esophageal fistula, and phrenic nerve palsy. For key questions 1-5 and 7, we will attempt to determine whether the comparative safety and effectiveness of the various therapies investigated differ among specific patient subgroups of interest. Patient characteristics to be assessed here include age, comorbidities, type of atrial fibrillation, previous pharmacological therapy failure, sex, enlarged left atrium, and high risk for stroke and bleeding events. Finally, key question 6 considers the comparative diagnostic accuracy efficacy, diagnostic thinking efficacy, therapeutic efficacy, and patient outcome efficacy of echocardiographic studies and other clinical parameters for predicting successful conversion, successful ablation, successful maintenance of sinus rhythm, and improved outcomes in patients with atrial fibrillation.

Abbreviations: AF = atrial fibrillation; KQ = key question

Methods

In developing this comprehensive review, we will apply the rules of evidence and evaluation of strength of evidence recommended by the Agency for Healthcare Research and Quality (AHRQ) in its Methods Guide for Effectiveness and Comparative Effectiveness Reviews (hereafter referred to as the Methods Guide).51 We will solicit feedback regarding conduct of the work (such as development of search strategies and identifying outcomes of key importance) from the Task Order Officer and the Technical Expert Panel. We will follow the methodology recommended to the Evidence-based Practice Centers for literature search strategies, inclusion/exclusion of studies in our review, abstract screening, data abstraction and management, assessment of methodological quality of individual studies, data synthesis, and grading of evidence for each KQ.

A. Criteria for Inclusion/Exclusion of Studies in the Review

We will apply the inclusion and exclusion criteria described in the Table below to studies identified by our literature search.

Table. Inclusion and exclusion criteria
PICOTS Element Inclusion Criteria Exclusion Criteria
Populations
  • Humans
  • Adults (age ≥18 years of age)
  • Patients with AF (includes atrial flutter)
  • Paroxysmal AF (recurrent episodes that self-terminate in less than 7 days)
  • Persistent AF (recurrent episodes that last more than 7 days)
  • Permanent AF (an ongoing, long-term episode)
  • Subgroups of potential interest include:
  • Patients stratified by age (≤40, 41–64, 65–74, 75–84, 85+)
  • Patients with different types of AF (paroxysmal, persistent, permanent)
  • Patients with specific comorbidities (heart failure, coronary artery disease, kidney disease, hypertrophic cardiomyopathy, thyroid disease, or pulmonary disease)
  • Patients who have previously failed a previous rate-control (KQ 3) or rhythm-control (KQ 5) pharmacological therapeutic strategy
  • Women
  • Patients with an enlarged left atrium
  • Patients at high risk for stroke and bleeding events (patients with diabetes, heart failure, and hypertension)
  • Patients who have known reversible causes of AF (including but not limited to postoperative, postmyocardial infarction, hyperthyroidism)
  • All subjects are <18 years of age, or some subjects are under <18 years of age but results are not broken down by age
Interventions
  • Pharmacological agents for rate control (KQs 1, 2, 3, and 7):
  • Beta-blockers (e.g., acebutolol, atenolol, bisoprolol, carvedilol, esmolol [acute rate lowering only], metoprolol, nadalol, nebivolol, timolol)
  • Calcium channel blockers (verapamil, diltiazem)
  • Other (digoxin, amiodarone, dronedarone)
  • Procedures for rate control (KQs 3 and 7)
  • AVN ablation and permanent pacemaker implantation
  • Pharmacological agents for rhythm control (KQs 4, 5, and 7):
  • Amiodarone
  • Disopyramide
  • Dofetilide
  • Dronedarone
  • Flecainide
  • Ibutilide [acute conversion only]
  • Propafenone
  • Sotalol
  • Procedures for rhythm control (KQs 5 and 7)
  • Electrical cardioversion
  • AF ablation by pulmonary vein isolation
    • Open surgical procedures
    • Minimally invasive procedures
    • Transcatheter procedures
  • Surgical Maze procedure
  • Cardiac resynchronization therapy
  • Echocardiography to predict successful treatment of AF (conversion, ablation, maintenance of sinus rhythm) (KQ 6)

None

Comparators
  • KQ 1: Other rate-control pharmacological agents
  • KQ 2: Other strict/lenient rate-control strategies
  • KQ 3: Other procedural, nonpharmacological, and other specific pharmacological rate-control therapies
  • KQ 4: Other antiarrhythmic agents
  • KQ 5: Other procedural, nonpharmacological, and other specific pharmacological rhythm-control therapies
  • KQ 6: Other clinical parameters for predicting successful conversion, successful ablation, successful maintenance of sinus rhythm, and improved outcomes in patients with AF (e.g., duration of AF, heart failure, coronary artery disease)
  • KQ 7: Other rhythm-control or rate-control therapies

None

Outcomes

Study assesses a patient-centered outcome of interest:

  • Intermediate outcomes:
  • Restoration of sinus rhythm (conversion)
  • Maintenance of sinus rhythm
  • Recurrence of AF at 12 months
  • Development of cardiomyopathy
  • Diagnostic accuracy efficacy, diagnostic thinking efficacy, therapeutic efficacy, and patient outcome efficacy of echocardiographic studies
  • Final outcomes:
  • Mortality (all-cause, cardiac)
  • Myocardial infarction
  • Cardiovascular hospitalizations
  • Heart failure symptoms
  • Control of AF symptoms (e.g., palpitations, exercise capacity)
  • Quality of life
  • Functional status
  • Stroke and other embolic events
  • Bleeding events
  • Adverse events:
  • Adverse events from drug therapies (e.g., hypotension, hypothyroidism and hyperthyroidism, arrhythmias [bradyarrhythmias, tachyarrhythmias, or proarrhythmias], allergic reactions, hepatotoxicity, neurotoxicity, pulmonary toxicity, ophthalmological toxicity, dermatological toxicity)
  • Procedural complications (including pulmonary vein stenosis, left atrial esophageal fistula, and phrenic nerve palsy)

Study does not include outcome of interest

Timing
  • Timing of followup will not be limiteda

None

Settings
  • Inpatient and outpatient

None

Study design
  • Original data
  • All sample sizes
  • RCTs, prospective and retrospective observational studies, or registries
  • Not a clinical study (e.g., editorial, nonsystematic review, letter to the editor, case series)
Publications
  • English-language only
  • Relevant systematic reviews, meta-analyses, or methods articles (used for background only)
  • Given the high volume of literature available in English-language publications, non–English-language articles will be excludedb

aFor all included studies, we will indicate the total number of patients enrolled and longest length (weeks or months) of followup if relevant.
bIt is the opinion of the investigators that the resources required to translate non–English-language articles would not be justified by the low potential likelihood of identifying relevant data unavailable from English-language sources. We will monitor the number of articles excluded at the abstract stage for English language and determine whether this exclusion criterion should be revisited.

Abbreviations: AF = atrial fibrillation; AVN = atrioventricular node; KQ = key question; PICOTS = populations, interventions, comparators, outcomes, timing, and settings; RCT = randomized controlled trial

B. Searching for the Evidence:  Literature Search Strategies for Identification of Relevant Studies To Answer the Key Questions

To identify relevant published literature, we will search PubMed®, EMBASE®, and the Cochrane Database of Systematic Reviews (CDSR), limiting the search to studies conducted in adults and published from January 1, 2000, to the present. We believe that the evidence published from 2000 on will represent the current standard of care for patients with AF and relevant comorbidities. Where possible, we will use existing validated search filters (such as the Clinical Queries Filters in PubMed®). An experienced search librarian will guide all searches. We will supplement the electronic searches with a manual search of citations from a set of key primary and review articles. The reference list for identified pivotal articles will be manually hand-searched and cross-referenced against our database, and additional relevant manuscripts will be retrieved. All citations will be imported into an electronic bibliographical database (EndNote® Version X4; Thomson Reuters, Philadelphia, PA).

As a mechanism to ascertain publication bias in recent studies, we will search ClinicalTrials.gov to identify completed but unpublished studies (we will also explore the possibility of publication bias specifically in our quantitative synthesis of the included literature through meta-analytic techniques). While the draft report is under peer review, we will update the search and include any eligible studies identified either during that search or through peer or public reviews in the final report.

We will use several approaches to identify relevant gray literature, including requests to drug and device manufacturers for scientific information packets and a search of U.S. Food and Drug Administration (FDA) device registration studies and new drug applications. We will also search study registries and conference abstracts for relevant articles from completed studies. Gray literature databases will include ClinicalTrials.gov; metaRegister of Controlled Trials; ClinicalStudyResults.org; the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal; and ProQuest COS Conference Papers Index.

For citations retrieved from MEDLINE®, EMBASE®, and the CDSR, two reviewers using prespecified inclusion/exclusion criteria will review titles and abstracts for potential relevance to the research questions. Articles included by either reviewer will undergo full-text screening. At the full-text screening stage, two independent reviewers must agree on a final inclusion/exclusion decision. Articles meeting eligibility criteria (see Table, above) will be included for data abstraction. All results will be tracked using the DistillerSR data synthesis software program (Evidence Partners Inc., Manotick, ON, Canada).

C. Data Abstraction and Data Management

The research team will create data abstraction forms for the KQs that will be programmed in the DistillerSR software. Based on their clinical and methodological expertise, a pair of researchers will be assigned to abstract data from each of the eligible articles. One researcher will abstract the data, and the second will over-read the article and the accompanying abstraction to check for accuracy and completeness. Disagreements will be resolved by consensus or by obtaining a third reviewer’s opinion if consensus cannot be reached. Guidance documents will be drafted and provided to the researchers to aid both reproducibility and standardization of data collection.

We will design the data abstraction forms for this project to collect the data required to evaluate the specified eligibility criteria for inclusion in this review, as well as demographic and other data needed to determine outcomes (intermediate, final, and adverse events outcomes). We will pay particular attention to describing the details of the treatment (e.g., pharmacotherapy dosing, methods of procedural therapies), patient characteristics (e.g., etiology of AF), and study design (e.g., RCT versus observational study) that may be related to outcomes. In addition, we will describe comparators carefully, as treatment standards may have changed during the period covered by the review. The safety outcomes will be framed to help identify adverse events, including those from drug therapies (e.g., hypotension; hypothyroidism and hyperthyroidism; arrhythmias [bradyarrhythmias, tachyarrhythmias, or proarrhythmias]; allergic reactions; hepatotoxicity; neurotoxicity; pulmonary toxicity) and those resulting from procedural complications. Data necessary for assessing quality and applicability, as described in the Methods Guide,51 will also be abstracted. Before they are used, abstraction-form templates will be pilot-tested with a sample of included articles to ensure that all relevant data elements are captured and that there is consistency/reproducibility between abstractors. Forms will be revised as necessary before full abstraction of all included articles.

D. Assessment of Methodological Quality of Individual Studies

We will assess methodological quality, or risk of bias, for each individual study by using the assessment instruments detailed in AHRQ’s Methods Guide.51 Briefly, we will rate each study as being of good, fair, or poor quality based on its adherence to well-accepted standard methodologies (e.g., QUADAS-255 for studies of diagnostic accuracy and the Downs and Black methodological quality assessment checklist52 for intervention studies). For all studies, the overall study quality will be assessed as follows:

  • Good (low risk of bias). These studies had the least bias, and the results were considered valid. These studies adhered to the commonly held concepts of high quality, including the following: a clear description of the population, setting, approaches, and comparison groups; appropriate measurement of outcomes; appropriate statistical and analytical methods and reporting; no reporting errors; a low dropout rate; and clear reporting of dropouts.
  • Fair. These studies were susceptible to some bias, but not enough to invalidate the results. They did not meet all the criteria required for a rating of good quality because they had some deficiencies, but no flaw was likely to cause major bias. The study may have been missing information, making it difficult to assess limitations and potential problems.
  • Poor (high risk of bias). These studies had significant flaws that might have invalidated the results. They had serious errors in design, analysis, or reporting; large amounts of missing information; or discrepancies in reporting.

The grading will be outcome-specific such that a given study that analyzes its primary outcome well but did an incomplete analysis of a secondary outcome would be assigned a different quality grade for each of the two outcomes. Studies of different designs will be graded within the context of their respective designs. Thus, RCTs will be graded good, fair, or poor, and observational studies will separately be graded good, fair, or poor.

E. Data Synthesis

We will begin by summarizing key features of the included studies for each KQ. To the degree that data are available, we will abstract information on study design; patient characteristics; clinical settings; interventions; and intermediate, final, and adverse event outcomes.

We will then determine the feasibility of completing a quantitative synthesis (i.e., meta-analysis). Feasibility depends on the volume of relevant literature, conceptual homogeneity of the studies, and completeness of the reporting of results. When a meta-analysis is appropriate, we will use random-effects models to synthesize the available evidence quantitatively. We will test for heterogeneity using graphical displays and test statistics (Q and I2 statistics), while recognizing that the ability of statistical methods to detect heterogeneity may be limited. For comparison, we will also perform fixed-effect meta-analyses. We will present summary estimates, standard errors, and confidence intervals. We anticipate that intervention effects may be heterogeneous. We hypothesize that the methodological quality of individual studies, study type, the characteristics of the comparator, and patients’ underlying clinical presentation will be associated with the intervention effects. If there are sufficient studies, we will perform subgroup analyses and/or meta-regression analyses to examine these hypotheses.

F. Grading the Evidence for Each Key Question

We will grade the strength of evidence for each outcome assessed; thus, the strength of evidence for two separate outcomes in a given study may be graded differently. The strength of evidence will be assessed using the approach described in the AHRQ’s Methods Guide.51,53 In brief, the approach requires assessment of four domains: risk of bias, consistency, directness, and precision. Additional domains to be used when appropriate are: coherence, dose-response association, impact of plausible residual confounders, strength of association (magnitude of effect), and publication bias. These domains will be considered qualitatively, and a summary rating of “high,” “moderate,” or “low” strength of evidence will be assigned for each outcome after discussion between two reviewers. In some cases, high, moderate, or low ratings will be impossible or imprudent to make, for example, when no evidence is available or when evidence on the outcome is too weak, sparse, or inconsistent to permit any conclusion. In these situations, a grade of “insufficient” will be assigned. This four-level rating scale is defined as follows:

  • High—High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
  • Moderate—Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.
  • Low—Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
  • Insufficient—Evidence either is unavailable or does not permit estimation of an effect.

G. Assessing Applicability

We will assess applicability across our KQs using the method described in AHRQ’s Methods Guide.51,54 In brief, this method uses the PICOTS format as a way to organize information relevant to applicability. The most important issue with respect to applicability is whether the outcomes are different across studies that recruit different populations (e.g., age groups, exclusions for comorbidities) or use different methods to implement the interventions of interest; that is, important characteristics are those that affect baseline (control group) rates of events, intervention group rates of events, or both. We will use a checklist to guide the assessment of applicability. We will use these data to evaluate the applicability to clinical practice, paying special attention to study eligibility criteria, demographic features of the enrolled population in comparison to the target population, characteristics of the intervention used in comparison with care models currently in use, the possibility of surgical learning curves, and clinical relevance and timing of the outcome measures. We will summarize issues of applicability qualitatively.

References

  1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285(18):2370-5. PMID: 11343485.
  2. Furberg CD, Psaty BM, Manolio TA, et al. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol 1994;74(3):236-41. PMID: 8037127.
  3. Krahn AD, Manfreda J, Tate RB, et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995;98(5):476-84. PMID: 7733127.
  4. Poole-Wilson PA, Swedberg K, Cleland JG, et al; Carvedilol Or Metoprolol European Trial Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362(9377):7-13. PMID: 12853193.
  5. Maggioni AP, Latini R, Carson PE, et al; Val-HeFT Investigators. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J 2005;149(3):548-57. PMID: 15864246.
  6. Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003;107(23):2920-5. PMID: 12771006.
  7. Singh SN, Tang XC, Singh BN, et al; SAFE-T Investigators. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program Substudy. J Am Coll Cardiol 2006;48(4):721-30. PMID: 16904540.
  8. Dorian P, Jung W, Newman D, et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol 2000;36(4):1303-9. PMID: 11028487.
  9. Chung MK, Shemanski L, Sherman DG, et al; AFFIRM Investigators. Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Functional Status Substudy. J Am Coll Cardiol 2005;46(10):1891-9. PMID: 16286177.
  10. Hagens VE, Ranchor AV, Van Sonderen E, et al; RACE Study Group. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation—results from the Rate Control Versus Electrical Cardioversion (RACE) Study. J Am Coll Cardiol 2004;43(2):241-7. PMID: 14736444.
  11. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22(8):983-8. PMID: 1866765.
  12. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27(10):1760-4. PMID: 8841325.
  13. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace 2006;8(9):651-745. PMID: 16987906.
  14. Institute of Medicine. 100 Initial Priority Topics for Comparative Effectiveness Research. June 2009. Available at: http://iom.edu/~/media/Files/Report%20Files/2009/ComparativeEffectivenessResearchPriorities/Stand%20Alone
    %20List%20of%20100%20CER%20Priorities%20-%20for%20web.pdf
     Exit Disclaimer. Accessed September 8, 2011.
  15. Brignole M, Gianfranchi L, Menozzi C, et al. Assessment of atrioventricular junction ablation and DDDR mode-switching pacemaker versus pharmacological treatment in patients with severely symptomatic paroxysmal atrial fibrillation: a randomized controlled study. Circulation 1997;96(8):2617-24. PMID: 9355902.
  16. Brignole M, Menozzi C, Gianfranchi L, et al. Assessment of atrioventricular junction ablation and VVIR pacemaker versus pharmacological treatment in patients with heart failure and chronic atrial fibrillation: a randomized, controlled study. Circulation 1998;98(10):953-60. PMID: 9737514.
  17. Kay GN, Ellenbogen KA, Giudici M, et al; APT Investigators. The Ablate and Pace Trial: a prospective study of catheter ablation of the AV conduction system and permanent pacemaker implantation for treatment of atrial fibrillation. J Interv Card Electrophysiol 1998;2(2):121-35. PMID: 9870004.
  18. Wood MA, Brown-Mahoney C, Kay GN, et al. Clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis. Circulation 2000;101(10):1138-44. PMID: 10715260.
  19. Wann LS, Curtis AB, January CT, et al; ACCF/AHA Task Force Members. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123(1):104-23. PMID: 21173346.
  20. Van Gelder IC, Groenveld HF, Crijns HJ, et al; RACE II Investigators. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362(15):1363-73. PMID: 20231232.
  21. Calkins H, Brugada J, Packer DL, et al. HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation developed in partnership with the European Heart Rhythm Association (EHRA) and the European Cardiac Arrhythmia Society (ECAS); in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), and the Society of Thoracic Surgeons (STS). Endorsed and approved by the governing bodies of the American College of Cardiology, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, and the Heart Rhythm Society. Europace 2007;9(6):335-79. PMID: 17599941.
  22. Krittayaphong R, Raungrattanaamporn O, Bhuripanyo K, et al. A randomized clinical trial of the efficacy of radiofrequency catheter ablation and amiodarone in the treatment of symptomatic atrial fibrillation. J Med Assoc Thai 2003;86 Suppl 1:S8-16. PMID: 12866763.
  23. Oral H, Pappone C, Chugh A, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 2006;354(9):934-41. PMID: 16510747.
  24. Pappone C, Augello G, Sala S, et al. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol 2006;48(11):2340-7. PMID: 17161267.
  25. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study). Eur Heart J 2006;27(2):216-21. PMID: 16214831.
  26. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA 2005;293(21):2634-40. PMID: 15928285.
  27. Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation 2008;118(24):2498-505. PMID: 19029470.
  28. Wilber DJ, Pappone C, Neuzil P, et al; ThermoCool AF Trial Investigators. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010;303(4):333-40. PMID: 20103757.
  29. Forleo GB, Mantica M, De Luca L, et al. Catheter ablation of atrial fibrillation in patients with diabetes mellitus type 2: results from a randomized study comparing pulmonary vein isolation versus antiarrhythmic drug therapy. J Cardiovasc Electrophysiol 2009;20(1):22-8. PMID: 18775050.
  30. Kong MH, Lopes RD, Piccini JP, et al. Surgical Maze procedure as a treatment for atrial fibrillation: a meta-analysis of randomized controlled trials. Cardiovasc Ther 2010;28(5):311-26. PMID: 20370795.
  31. Gasparini M, Steinberg JS, Arshad A, et al. Resumption of sinus rhythm in patients with heart failure and permanent atrial fibrillation undergoing cardiac resynchronization therapy: a longitudinal observational study. Eur Heart J 2010;31(8):976-83. PMID: 20071325.
  32. Hauck M, Bauer A, Voss F, et al. Effect of cardiac resynchronization therapy on conversion of persistent atrial fibrillation to sinus rhythm. Clin Res Cardiol 2009;98(3):189-94. PMID: 19034378.
  33. Lellouche N, De Diego C, Vaseghi M, et al. Cardiac resynchronization therapy response is associated with shorter duration of atrial fibrillation. Pacing Clin Electrophysiol 2007;30(11):1363-8. PMID: 17976100.
  34. Hugl B, Bruns HJ, Unterberg-Buchwald C, et al. Atrial fibrillation burden during the post-implant period after crt using device-based diagnostics. J Cardiovasc Electrophysiol 2006;17(8):813-7. PMID: 16903958.
  35. Hoppe UC, Casares JM, Eiskjaer H, et al. Effect of cardiac resynchronization on the incidence of atrial fibrillation in patients with severe heart failure. Circulation 2006;114(1):18-25. PMID: 16801461.
  36. Yilmaz A, Geuzebroek GS, Van Putte BP, et al. Completely thoracoscopic pulmonary vein isolation with ganglionic plexus ablation and left atrial appendage amputation for treatment of atrial fibrillation. Eur J Cardiothorac Surg 2010;38(3):356-60. PMID: 20227287.
  37. Pokushalov E, Romanov A, Artyomenko S, et al. Ganglionated plexi ablation for longstanding persistent atrial fibrillation. Europace 2010;12(3):342-6. PMID: 20173210.
  38. Han FT, Kasirajan V, Kowalski M, et al. Results of a minimally invasive surgical pulmonary vein isolation and ganglionic plexi ablation for atrial fibrillation: single-center experience with 12-month follow-up. Circ Arrhythm Electrophysiol 2009;2(4):370-7. PMID: 19808492.
  39. Pokushalov E, Turov A, Shugayev P, et al. Catheter ablation of left atrial ganglionated plexi for atrial fibrillation. Asian Cardiovasc Thorac Ann 2008;16(3):194-201. PMID: 18515667.
  40. Frick M, Frykman V, Jensen-Urstad M, et al. Factors predicting success rate and recurrence of atrial fibrillation after first electrical cardioversion in patients with persistent atrial fibrillation. Clin Cardiol 2001;24(3):238-44. PMID: 11288971.
  41. Okçün B, Yigit Z, Küçükoglu MS, et al. Predictors for maintenance of sinus rhythm after cardioversion in patients with nonvalvular atrial fibrillation. Echocardiography 2002;19(5):351-7. PMID: 12174197.
  42. Olshansky B, Heller EN, Mitchell LB, et al. Are transthoracic echocardiographic parameters associated with atrial fibrillation recurrence or stroke? Results from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study. J Am Coll Cardiol 2005;45(12):2026-33. PMID: 15963405.
  43. Pálinkás A, Antonielli E, Picano E, et al. Clinical value of left atrial appendage flow velocity for predicting of cardioversion success in patients with non-valvular atrial fibrillation. Eur Heart J 2001;22(23):2201-8. PMID: 11913482.
  44. Verhorst PM, Kamp O, Welling RC, et al. Transesophageal echocardiographic predictors for maintenance of sinus rhythm after electrical cardioversion of atrial fibrillation. Am J Cardiol 1997;79(10):1355-9. PMID: 9165157.
  45. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation—Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000;356(9244):1789-94. PMID: 11117910.
  46. Wyse DG, Waldo AL, DiMarco JP, et al; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347(23):1825-33. PMID: 12466506.
  47. Van Gelder IC, Hagens VE, Bosker HA, et al; Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347(23):1834-40. PMID: 12466507.
  48. Carlsson J, Miketic S, Windeler J, et al; STAF Investigators. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41(10):1690-6. PMID: 12767648.
  49. Opolski G, Torbicki A, Kosior DA, et al; Investigators of the Polish HOT CAFÉ Trial. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest 2004;126(2):476-86. PMID: 15302734.
  50. Roy D, Talajic M, Nattel S, et al; Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358(25):2667-77. PMID: 18565859.
  51. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; August 2011. AHRQ Publication No. 10(11)-EHC063-EF. Chapters available at: www.effectivehealthcare.ahrq.gov).
  52. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998;52(6):377-84. PMID: 9764259.
  53. Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions-Agency for Healthcare Research and Quality and the Effective Health Care Program. J Clin Epidemiol 2010;63(5):513-23. PMID: 19595577.
  54. Atkins D, Chang SM, Gartlehner G, et al. Assessing applicability when comparing medical interventions: AHRQ and the Effective Health Care Program. J Clin Epidemiol 2011;64(11):1198-207. PMID: 21463926.
  55. Whiting PF, Rutjes AW, Westwood ME, et al; QUADUS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011;155(8):529-536. PMID: 22007046.

Definition of Terms

ACC American College of Cardiology
ACCF American College of Cardiology Foundation
AF atrial fibrillation
AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management
AHA American Heart Association
AHRQ Agency for Healthcare Research and Quality
AVN atrioventricular node
bpm beats per minute
CARE-HF Cardiac REsynchronization in Heart Failure
CDSR Cochrane Database of Systematic Reviews
CRT cardiac resynchronization therapy
ESC European Society of Cardiology
FDA U.S. Food and Drug Administration
HRS Heart Rhythm Society
ICTRP International Clinical Trials Registry Platform
KQ Key Question
PICOTS Populations, Interventions, Comparators, Outcomes, Timing, and Settings
RACE-II Rate Control Efficacy in Permanent Atrial Fibrillation-II
RCT(s) randomized controlled trial(s)
WHO World Health Organization

Summary of Protocol Amendments

Date and Section Original Protocol Revised Protocol Rationale

5/22/2012
I. Background, “Rhythm Control,” last 2 paragraphs

Finally, a few small observational studies have suggested that autonomic ganglionic plexi ablation or denervation may play a role in treating AF, but these findings have not been confirmed by RCTs, and uncertainty exists as to the comparative safety and effectiveness of these strategies.36-39
In selecting treatment modalities most likely to produce successful results in rhythm control, few diagnostic studies or risk models exist to guide practicing clinicians in predicting response to available therapies in individual patients. Previous studies have examined the role of clinical factors (such as age, existence of congestive heart failure or left ventricular dysfunction, diabetes, etc.), duration of AF, and/or prior attempts at cardioversion in predicting response to therapies, especially response to electrical and pharmacological cardioversion.40,41 Additionally, imaging parameters—particularly echocardiographic criteria such as left ventricular wall thickness, left atrial dimension, left atrial appendage flow, and left ventricular function—have been examined as potential risk variables in the prediction of successful rhythm-control strategies.42-44 However, these clinical and imaging parameters have not been systematically reviewed to determine their role or potential evidence gaps for their use in routine clinical practice. Data are also lacking on clinical and echocardiographic predictors of response to catheter ablation of AF. Data synthesis on this topic would be of great benefit to practicing physicians in helping them select the best patients for each available therapeutic modality.

Text deleted

This text was specific to discussion of the original KQ 6, and was deleted to reflect the removal of that KQ from the review (see below).

5/22/2012
II. Key Questions, transition from KQ 3 to KQ 4

Our next three KQs focus specifically on rhythm-control therapies:

Our next two KQs focus specifically on rhythm-control therapies:

This text was revised to reflect the removal of the original KQ 6 (see below).

5/22/2012
II. Key Questions, KQ 6 et passim

KQ 6: What are the comparative diagnostic accuracy, diagnostic thinking, therapeutic, and patient outcome efficacy of echocardiographic studies and other clinical parameters for predicting successful conversion, successful ablation, successful maintenance of sinus rhythm, and improved outcomes in patients with atrial fibrillation?

KQ 6 has been removed; the previous KQ 7 has been designated as KQ 6.

After initial screening of the literature indicated a very large body of literature for this review, a scoping decision was reached with AHRQ and the TEP to remove KQ 6 from consideration within this CER.
To reflect the removal of the original KQ 6, all references to the former KQ 7 have been changed to KQ 6 throughout the protocol, and elements specific to the former KQ 6 have been removed.

5/22/2012
II. Key Questions, PICOTS, Interventions, “Pharmaco-logical agents for rhythm control”

 

Bullets added:

  • Beta-blockers (e.g., acebutolol, atenolol, bisoprolol, carvedilol, esmolol [acute rate lowering only], metoprolol, nadalol, nebivolol, timolol)
  • Calcium channel blockers (verapamil, diltiazem)

Clarification that these drugs may be considered as rhythm control agents, as well as rate control agents

5/22/2012
II. Key Questions, PICOTS, Interventions, “Echocardio-graphy…”

  • Echocardiography to predict successful treatment of AF (conversion, ablation, maintenance of sinus rhythm) (KQ6)

Bullet point deleted

Intervention specific to former KQ 6 has been removed.

5/22/2012
II. Key Questions, PICOTS, Comparators

 

Added “of interest” to each previously listed comparator

Text added to specify that acceptable comparators are those therapies specifically listed as interventions of interest

5/22/2012
II. Key Questions, PICOTS, Patient-Centered Outcome Measures

  • Diagnostic accuracy efficacy, diagnostic thinking efficacy, therapeutic efficacy, and patient outcome efficacy of echocardiographic studies (KQ6 only)

Bullet point deleted

Outcomes specific to former KQ 6 have been removed.

5/22/2012
III. Analytic Framework, Figure 2

Interventions/Comparators:
Instruments for predicting successful conversion, successful ablation, successful maintenance of sinus rhythm, and improved outcomes in patients:

  • Echocardiographic parameters
  • Clinical parameters

Outcome Measures:

  • Diagnostic accuracy efficacy
  • Diagnostic thinking efficacy
  • Therapeutic efficacy
  • Patient outcome efficacy

Figure components deleted

Figure components specific to former KQ 6 have been removed.

5/22/2012
IV. Methods, Table. Inclusion and exclusion criteria, “Interventions” row, “Inclusion Criteria” column

 

Added bullets added under the category “Pharmacological agents for rhythm control”

  • Beta-blockers (e.g., acebutolol, atenolol, bisoprolol, carvedilol, esmolol [acute rate lowering only], metoprolol, nadalol, nebivolol, timolol)
  • Calcium channel blockers (verapamil, diltiazem)

Clarification that these listed drugs may be considered as rhythm control agents, as well as rate control agents

5/22/2012
IV. Methods, Table. Inclusion and exclusion criteria, “Interventions” row, “Inclusion Criteria” column

  • Echocardiography to predict successful treatment of AF (conversion, ablation, maintenance of sinus rhythm) (KQ 6)

Bullet point deleted

Interventions specific to former KQ 6 have been removed.

5/22/2012
IV. Methods, Table. Inclusion and exclusion criteria, “Interventions” row, “Exclusion Criteria” column

None

  • Studies comparing different imaging or mapping techniques (focus is on comparisons between treatment strategies)
  • Studies of intracardiac echocardiography, different ablation sources and energies, different techniques of septal puncture, and different diagnostic maneuvers during an ablation procedure
  • Studies of atrial flutter ablation, ablation for post-pulmonary vein isolation tachycardias including atrial flutter, and studies of internal cardioversion, transesophageal cardioversion and patient-enabled cardioversion using an ICD
  • Studies investigating use of antiarrhythmic drugs peri-ablation or after failed pulmonary vein isolation
  • Studies of any intervention not available in the United States, including intravenous formulations of medications that are available in the U.S. only in an oral form.
  • Studies with a majority of patients taking an antiarrhythmic drug not specified as an intervention of interest, unless the study also includes a comparison between a drug of interest and a control arm.

New text was added to explicitly clarify the exclusion of studies that do not include a comparison between treatment strategies, do not present data for interventions within the scope of the KQs, or address interventions that are not in common use or are not available in the United States.

5/22/2012
IV. Methods, Table. Inclusion and exclusion criteria, “Comparators” row, “Inclusion Criteria” column

 

Added “of interest” to each previously listed comparator

Text added to specify that acceptable comparators are those therapies specifically listed as interventions of interest

5/22/2012
IV. Methods, Table. Inclusion and exclusion criteria, “Study design” row, “Inclusion Criteria” column

  • Original data
  • All sample sizes
  • RCTs, prospective and retrospective observational studies, or registries
  • Original data
  • KQ 1: RCTs (≥ 20 patients)
  • KQ 2: RCTs (≥ 20 patients) and prospective and retrospective observational studies or registries (≥ 100 patients)
  • KQ 3: RCTs (≥ 20 patients)
  • KQ 4: RCTs (≥ 20 patients)
  • KQ 5: RCTs (≥ 20 patients) and (for studies related to CRT) prospective and retrospective observational studies or registries (≥ 100 patients)
  • KQ 6: RCTs (≥ 20 patients)

KQs 1, 3-4, and 6 were limited to RCT study designs with ≥ 20 patients due to the availability of a sizeable quantity of RCT data in these clinical areas and the intrinsic risk of bias in observational studies. For those KQs with a small body of RCT data available (KQ 2 and KQ 5 studies related to CRT), observational studies with ≥ 100 patients will also be considered.

5/22/2012
IV. Methods, “Searching” section, 3rd paragraph, last sentence

Gray literature databases will include ClinicalTrials.gov; metaRegister of Controlled Trials; ClinicalStudyResults.org; the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal; and ProQuest COS Conference Papers Index.

Gray literature databases will include ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal; and ProQuest COS Conference Papers Index.

Text updated to reflect one database that is no longer available (ClinicalStudyResults.org Exit Disclaimer) and the inclusion of the metaRegister of Controlled Trials database information within the WHO ICTRP.

5/22/2012
IV. Methods “Assessment of Methodological Quality,” 1st paragraph, 1st 2 sentences

We will assess methodological quality, or risk of bias, for each individual study by using the assessment instruments detailed in AHRQ’s Methods Guide.51 Briefly, we will rate each study as being of good, fair, or poor quality based on its adherence to well-accepted standard methodologies (e.g., QUADAS-255 for studies of diagnostic accuracy and Downs and Black methodological quality assessment checklist52 for intervention studies).

We will assess methodological quality, or risk of bias, for each individual study by using the assessment instruments detailed in AHRQ’s Methods Guide.51 Briefly, we will rate each study as being of good, fair, or poor quality based on its adherence to well-accepted standard methodologies.

The quality assessment approach was updated to simplify and to reflect the removal of the original KQ6, which differed from the others in that it addressed diagnostic accuracy. For all KQs, it will now be appropriate to use the assessments detailed in AHRQ’s Methods Guide.

Review of Key Questions

For all EPC reviews, key questions were reviewed and refined as needed by the EPC with input from Key Informants and the Technical Expert Panel (TEP) to assure that the questions are specific and explicit about what information is being reviewed. In addition, for Comparative Effectiveness reviews, the key questions were posted for public comment and finalized by the EPC after review of the comments.

Key Informants

Key Informants are the end-users of research, including patients and caregivers, practicing clinicians, relevant professional and consumer organizations, purchasers of health care, and others with experience in making health care decisions. Within the EPC program, the Key Informant role is to provide input into identifying the Key Questions for research that will inform health care decisions. The EPC solicits input from Key Informants when developing questions for systematic review or when identifying high-priority research gaps and needed new research. Key Informants are not involved in analyzing the evidence or writing the report and have not reviewed the report, except as given the opportunity to do so through the peer or public review mechanism.

Key Informants must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their role as end-users, individuals are invited to serve as Key Informants and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

Technical Experts

Technical Experts comprise a multidisciplinary group of clinical, content, and methodological experts who provide input in defining populations, interventions, comparisons, or outcomes as well as identifying particular studies or databases to search. They are selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicted opinions are common and perceived as healthy scientific discourse that results in a thoughtful, relevant systematic review. Therefore study questions, design and/or methodological approaches do not necessarily represent the views of individual technical and content experts. Technical Experts provide information to the EPC to identify literature search strategies and recommend approaches to specific issues as requested by the EPC. Technical Experts do not do analysis of any kind nor contribute to the writing of the report and have not reviewed the report, except as given the opportunity to do so through the public review mechanism.

Technical Experts must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals are invited to serve as Technical Experts and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

Peer Reviewers

Peer reviewers are invited to provide written comments on the draft report based on their clinical, content, or methodological expertise. Peer review comments on the preliminary draft of the report are considered by the EPC in preparation of the final draft of the report. Peer reviewers do not participate in writing or editing of the final report or other products. The synthesis of the scientific literature presented in the final report does not necessarily represent the views of individual reviewers. The dispositions of the peer review comments are documented and will, for CERs and Technical briefs, be published 3 months after the publication of the Evidence report.

Potential Reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Invited Peer Reviewers may not have any financial conflict of interest greater than $10,000. Peer reviewers who disclose potential business or professional conflicts of interest may submit comments on draft reports through the public comment mechanism.

EPC team disclosures

None of the EPC team members has any affiliations or financial involvement that conflicts with the material presented in this document.

Role of the Funder

This project was funded under Contract No. 290-07-10066-I from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The Task Order Officer reviewed contract deliverables for adherence to contract requirements, including the objectivity and independence of the research process and the methodological quality of the report. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Return to Top of Page