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Original Contribution |

Comparison of Antiarrhythmic Drug Therapy and Radiofrequency Catheter Ablation in Patients With Paroxysmal Atrial Fibrillation:  A Randomized Controlled Trial FREE

David J. Wilber, MD; Carlo Pappone, MD, PhD; Petr Neuzil, MD; Angelo De Paola, MD; Frank Marchlinski, MD; Andrea Natale, MD; Laurent Macle, MD; Emile G. Daoud, MD; Hugh Calkins, MD; Burr Hall, MD; Vivek Reddy, MD; Giuseppe Augello, MD; Matthew R. Reynolds, MD, MSc; Chandan Vinekar, MS; Christine Y. Liu, MPH; Scott M. Berry, PhD; Donald A. Berry, PhD; for the ThermoCool AF Trial Investigators
[+] Author Affiliations

Author Affiliations: Cardiovascular Institute, Department of Medicine, Loyola University Medical Center, Maywood, Illinois (Dr Wilber); Department of Medicine, Hospital San Raffaele, Milan, Italy (Drs Pappone and Augello); Department of Medicine, Na Homolce Hospital, Prague, Czech Republic (Drs Neuzil and Reddy); Department of Medicine, Hospital Sao Paulo/UNIFESP, Sao Paulo, Brazil (Dr De Paola); Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia (Dr Marchlinski); Department of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (Dr Natale); Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada (Dr Macle); Department of Medicine, Ohio State University, Columbus (Dr Daoud); Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland (Dr Calkins); Department of Medicine, University of Rochester Medical Center, Rochester, New York (Dr Hall); Harvard Clinical Research Institute, Boston, Massachusetts (Dr Reynolds); Biosense Webster, Diamond Bar, California (Mr Vinekar and Ms Liu); Berry Consultants, College Station, Texas (Dr S. Berry); and University of Texas M.D. Anderson Cancer Center, Houston (Dr D. Berry).


JAMA. 2010;303(4):333-340. doi:10.1001/jama.2009.2029.
Text Size: A A A
Published online

Context Antiarrhythmic drugs are commonly used for prevention of recurrent atrial fibrillation (AF) despite inconsistent efficacy and frequent adverse effects. Catheter ablation has been proposed as an alternative treatment for paroxysmal AF.

Objective To determine the efficacy of catheter ablation compared with antiarrhythmic drug therapy (ADT) in treating symptomatic paroxysmal AF.

Design, Setting, and Participants A prospective, multicenter, randomized (2:1), unblinded, Bayesian-designed study conducted at 19 hospitals of 167 patients who did not respond to at least 1 antiarrhythmic drug and who experienced at least 3 AF episodes within 6 months before randomization. Enrollment occurred between October 25, 2004, and October 11, 2007, with the last follow-up on January 19, 2009.

Intervention Catheter ablation (n = 106) or ADT (n = 61), with assessment for effectiveness in a comparable 9-month follow-up period.

Main Outcome Measures Time to protocol-defined treatment failure. The proportion of patients who experienced major treatment-related adverse events within 30 days of catheter ablation or ADT was also reported.

Results At the end of the 9-month effectiveness evaluation period, 66% of patients in the catheter ablation group remained free from protocol-defined treatment failure compared with 16% of patients treated with ADT. The hazard ratio of catheter ablation to ADT was 0.30 (95% confidence interval, 0.19-0.47; P < .001). Major 30-day treatment-related adverse events occurred in 5 of 57 patients (8.8%) treated with ADT and 5 of 103 patients (4.9%) treated with catheter ablation. Mean quality of life scores improved significantly in patients treated by catheter ablation compared with ADT at 3 months; improvement was maintained during the course of the study.

Conclusion Among patients with paroxysmal AF who had not responded to at least 1 antiarrhythmic drug, the use of catheter ablation compared with ADT resulted in a longer time to treatment failure during the 9-month follow-up period.

Trial Registration clinicaltrials.gov Identifier: NCT00116428

Figures in this Article

Atrial fibrillation (AF) represents an important public health problem. Patients with AF have an increased long-term risk of stroke, heart failure, and all-cause mortality.14 Furthermore, patients with AF describe a considerably impaired quality of life (QOL) that is independent of the severity of the disease.5,6 Restoration and maintenance of normal sinus rhythm following treatment directly correlates with improved QOL in these patients.58

Although antiarrhythmic drugs are generally used as first-line therapy to treat patients with AF, effectiveness remains inconsistent. The likelihood of AF recurrence within 6 to 12 months approaches 50% with most drugs.911 Antiarrhythmic drugs are also associated with cumulative adverse effects over time.1 Catheter ablation has accordingly become an alternative therapy for AF.12 Several recent studies have compared antiarrhythmic drug therapy (ADT) with catheter ablation.1316 These investigations were characterized by small study populations, variable entry criteria and definitions of success, and were conducted in a single or limited number of centers.

This prospective, multicenter, randomized study was designed to compare catheter ablation with ADT in patients with symptomatic AF who had not improved with at least 1 drug. Our primary goal was to evaluate freedom from symptomatic AF recurrence following treatment. Total atrial arrhythmia recurrence during follow-up was also evaluated.

The study protocol was approved by the institutional review board or ethics committee at each of the 19 centers (15 in the United States, 2 in Europe, and 1 each in Canada and Latin America). All patients enrolled in the study provided written informed consent.

Study Population

At each center, potential study candidates with the diagnosis of AF were identified from outpatient and inpatient discharge logs of the respective institutions or by physician or self-referrals in response to institutional review board–approved study announcements. Enrollment required at least 3 symptomatic AF episodes (≥1 episode verified by electrocardiogram) within the 6 months before randomization, and not responding to at least 1 antiarrhythmic drug (class I, class III, or atrioventricular nodal blocker).

Exclusion criteria included patients with AF of more than 30 days in duration, age younger than 18 years, an ejection fraction of less than 40%, previous ablation for AF, documented left atrial thrombus, amiodarone therapy in the previous 6 months, New York Heart Association class III (marked limitation in activity due to symptoms) or IV (severe limitations), myocardial infarction within the previous 2 months, coronary artery bypass graft procedure in the previous 6 months, thromboembolic event in the previous 12 months, severe pulmonary disease, a prior valvular cardiac surgical procedure, presence of an implanted cardioverter-defibrillator, contraindication to antiarrhythmic or anticoagulation medications, life expectancy of less than 12 months, and left atrial size of at least 50 mm in the parasternal long axis view.

Study Design

Patients were randomly assigned 2:1 to ablation or a previously unused antiarrhythmic drug (classes I or III). Upon enrollment, participants were assigned a sequential identification number at each site and a corresponding sealed envelope was opened. Randomization sequences were generated by the sponsor statistician by using SAS version 8.2 (SAS Institute Inc, Cary, North Carolina) and stratified by site with block size of 11 (7 to catheter ablation and 4 to ADT).

Protocol

After randomization, patients in the catheter ablation group were observed in the clinic at 1, 3, 6, 9, and 12 months, and patients in the ADT group were observed at 5 to 10 days, 11 to 21 days, and 3, 6, and 9 months. Patients were followed up for comparable 9-month effectiveness evaluation period after a 3-month blanking (healing and stabilization) period for those randomized to ablation (days 91-361) and, after a 14-day dose-titration period, for those randomized to the ADT group. Electrocardiograms were obtained at all follow-up visits. Transtelephonic monitoring (MicroER; LifeWatch Inc, Rosemont, Illinois) was performed during the 9-month period for patients in both groups. Patients were required to transmit all symptomatic cardiac episodes. They were also required to provide additional scheduled transmissions irrespective of symptoms: weekly for the first 8 weeks, then monthly until the final visit. Holter monitoring (DigiTrak Plus; Phillips Medical Systems, Andover, Massachusetts) was conducted at the baseline and final visit for all patients. For patients undergoing ablation, a computed tomography (CT) scan or magnetic resonance imaging (MRI) scan was required within 30 days before the procedure and at 3 months and 12 months after the procedure. Pulmonary vein (PV) stenosis identified by CT or MRI scan was defined as at least 70% reduction of the PV diameter compared with the baseline scan. Independent core laboratories were used to process and analyze transtelephonic, Holter monitors, and CT or MRI scan results. An independent data and safety monitoring committee reviewed and adjudicated causality of all adverse events.

ADT Group

Patients randomized to the ADT group received a not previously administered, Food and Drug Administration–approved medication for treating AF (dofetilide, flecainide, propafenone, sotalol, or quinidine). The choice of drug was at the discretion of the investigator. Dosages were based on recommendations from the American College of Cardiology/American Heart Association/European Society of Cardiology 2001 Practice Guidelines for Management of Patients With Atrial Fibrillation.1 The drug and dosage at the end of the titration period were then maintained throughout the study. Amiodarone was not allowed per study protocol. Patients in the ADT group were allowed to crossover and undergo an ablation procedure after 90 days of therapy if the treatment failed.

Catheter Ablation Group

In all patients, PV isolation with confirmation of entrance block was required.12 The ablation catheter (NaviStar ThermoCool Irrigated Tip Catheter; Biosense Webster, Diamond Bar, California) was introduced under fluoroscopic guidance, and the Carto Navigation System (Biosense Webster) was used to map and document the placement of radiofrequency lesions. The PVs were isolated by circumferential lesions. Additional ablation was allowed at investigator discretion and included left atrial linear lesions, ablation at sites with electrogram fractionation, and cavotricuspid isthmus ablation. Infusion of isoproterenol (≤20 μg/min) was recommended postablation to confirm that all AF foci had been eliminated or isolated. After the initial procedure, patients in the catheter ablation group were allowed up to 2 repeat ablation procedures within 80 days. At the discretion of the investigator, a previously ineffective drug could be continued during the effectiveness evaluation period. Following ablation, anticoagulation with warfarin was required for the initial 3 months. Subsequent use of anticoagulation during the effectiveness evaluation period followed current guidelines.1

Primary End Point

The primary end point was freedom from protocol-defined treatment failure, which included documented symptomatic paroxysmal AF during the effectiveness evaluation period. Patients in the ablation group with repeat ablation after day 80 after the initial ablation, absence of entrance block confirmed in all PVs at the end of the ablation procedure, or changes in specified drug regimen postblanking (including class I/III drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and atrioventricular nodal blocker) were also considered treatment failures, even if they remained free from symptomatic paroxysmal AF. In the ADT group, an adverse event requiring discontinuation of the assigned drug was also considered a treatment failure.

Safety Outcomes

Major treatment-related adverse events were defined as those that occurred within 30 days of the ablation procedure or within 30 days following initiation of drug therapy. Prespecified major adverse events included death, myocardial infarction, PV stenosis, diaphragmatic paralysis, atrio-esophageal fistula, transient ischemic attack, thromboembolic events, pericarditis, cardiac tamponade, pericardial effusion, pneumothorax, vascular access complications, pulmonary edema, or congestive heart failure, heart block, life-threatening ventricular arrhythmias, and intolerance to assigned antiarrhythmic drug requiring discontinuation.

Additional Comparisons

Additional comparisons included freedom from symptomatic atrial arrhythmia (AF, atrial tachycardia, atrial flutter), freedom from any atrial arrhythmia (symptomatic or asymptomatic), and QOL outcomes. Instruments used to evaluate QOL included the 36-item Short-Form Health Survey (SF-36), Version 2,17 and the AF Symptom Frequency and Severity Checklist.18

Statistical Methods

The statistical design was prospective and Bayesian. The protocol-defined primary statistical analysis of the primary end points was Bayesian.1921 Study success required a probability of superiority of catheter ablation over ADT in the primary end point at the final analysis of at least 98% to control the type I error rate at no more than 2.5%, which was verified by simulations. Maximal sample size was 230 patients with preplanned interim analyses to occur after accruing 150, 175, and 200 patients. If at any interim Bayesian analysis the predictive probability of eventual study success (>98% probability of superiority when all patients have full follow-up) based on the currently accrued patients (including longitudinal modeling of those patients with <9 months of follow-up) was at least 99%, accrual would stop with study success declared. If the predictive probability of eventual study success was less than 99% but at least 90% at the 150 patient analysis, or 80% at the 175 and 200 patient analyses, accrual would end, but patient follow-up would continue until such time that study success could be declared. If the predictive probabilities of study success for the current sample size and also for the maximum sample size (230 patients) were less than 1% for the 150, 175, or 200 patient analyses, the trial would stop for futility.

The conclusion of the primary statistical analysis was Bayesian predictive and posterior probabilities at the interim analysis at the time the trial was stopped. The probability of superiority based on the study results updated with full follow-up through the 9-month effectiveness period for all patients was also assessed. This calculation was based on intention-to-treat using multiple imputations for the patients who dropped out; this latter analysis was specified in the protocol for patients who did not have 9 months of follow-up. We used 3 parameter piecewise exponential models, with breaks at 2 weeks and 2 months, for imputation within each treatment group. The posterior distributions of the 3 parameters included all available information from patients within the respective treatment group. Patients with missing data were included in the final analysis of 9-month success using Bayesian multiple imputations from the 3 parameter exponential models.

For the updated results, we present the more conventional frequentist measures of P values and confidence intervals (CIs). These are provided without adjustments for interim analyses and so are “nominal” in the sense that they assume that the final sample size was fixed in advance. Continuous variables were expressed as mean (95% CI) and were compared using t tests or Wilcoxon rank sum test as appropriate. Categorical variables were compared with Fisher exact tests.

Additional analyses include Kaplan-Meier representations for time-to-event data. Univariable and multivariable Cox regression analyses were conducted to identify and account for factors predictive of time to failure: age, sex, structural heart disease, diabetes, hypertension, number of symptomatic AF episodes, duration of AF history, prior failure of class II or IV drug only, left atrial dimension, and study center. Factors with P<.05 were included in the final multivariable model. All tests of significance were 2-sided, with P<.05 considered statistically significant.

In the Kaplan-Meier and Cox regression results presented, 8 patients who did not receive assigned treatment were excluded. The remaining patients were censored at the end of the 9-month evaluation period or last known follow-up, whichever occurred first. Analyses were also run in which the 8 randomized but untreated patients were handled in a “worst case” scenario. Specifically, nontreated test patients were assumed to have an event (failure) on day 1, and nontreated control patients were assumed to not have an event (success) through day 270. The Kaplan-Meier and Cox regression results did not appreciably change and conclusions did not change from those generated when the 8 patients were excluded.

The Bayesian analysis was conducted by using Fortran 90 (Intel Fortran 11.0 compiler). The code was written and verified by Berry Consultants and went through the review process by the Center for Devices and Radiological Health division of the Food and Drug Administration. The frequentist analyses were conducted by using SAS version 9.1.3 (SAS Institute Inc, Cary, North Carolina).

Patient Characteristics

Between October 25, 2004, and October 11, 2007, 167 patients were enrolled in the study, with the last follow-up performed on January 19, 2009. Sixty-one and 106 patients were randomized to ADT and catheter ablation groups, respectively. Five patients from the ADT group and 3 patients from the catheter ablation group did not complete the assigned treatment (Figure 1). Overall, the mean age was 55.7 (95% CI, 54.1-57.4) years and 33.5% of the patients were women. Patients had a history of symptomatic AF for 5.7 (95% CI, 4.8-6.6) years and had discontinued an average of 1.3 (95% CI, 1.1-1.4) antiarrhythmic drugs before enrollment. The 2 groups were well matched with respect to baseline characteristics (Table 1). The median (interquartile range) for follow-up times in the catheter ablation and ADT groups were 12.5 (11.9-13.1) months and 14.3 (9.4-15.5) months, respectively.

Place holder to copy figure label and caption
Figure 1. Patient Flow Diagram
Graphic Jump Location

AF indicates atrial fibrillation.

Table Graphic Jump LocationTable 1. Baseline Patient Characteristicsa
Interim Analysis and Bayesian Probabilities

The first preplanned interim analysis was conducted after accruing 150 patients. The trial was stopped (although follow-up was continued) when this analysis showed the predictive probability of success to be 99.9%. This was more than the protocol-specified boundary of 99% and enabled an immediate claim of study success (ie, superiority of catheter ablation over ADT). Based on the updated study results of 167 patients (including multiple imputation for the 8 patients who did not receive assigned treatment), the probability of superiority was 99.9%.

Initial Treatment

Most patients in the ADT group were assigned to either flecainide (20/56 [36%]) or propafenone (23/56 [41%]). Sotalol and dofetilide were assigned to 11 and 2 patients, respectively. For the catheter ablation group, confirmation of entrance block following PV isolation was achieved in all patients. The mean procedure time was 208 (95% CI, 191.2-224.8) minutes and the mean fluoroscopy time was 48.6 (95% CI, 40.5-56.7) minutes. Of the 103 patients undergoing catheter ablation procedures, linear ablation of the cavotricuspid isthmus was performed in 37 patients (35.9%). At least 1 left atrial linear lesion (including mitral isthmus and roof lines) was performed in 23 patients (22.3%). The superior vena cava was targeted in 17 patients (16.5%) and other left or right atrial foci were targeted in 17 patients (16.5%). A repeat ablation procedure was performed in 13 patients (12.6%) within 80 days of the initial catheter ablation procedure.

Effectiveness Outcome Analyses

Kaplan-Meier curves for the effectiveness outcomes are shown in Figure 2. At the end of the 9-month effectiveness evaluation period, 66% of patients in the catheter ablation group remained free from protocol-defined treatment failure vs 16% of patients treated with ADT (hazard ratio [HR], 0.30; 95% CI, 0.19-0.47; P < .001). Similarly, 70% of patients treated by catheter ablation remained free of symptomatic recurrent atrial arrhythmia vs 19% of patients treated with ADT (HR, 0.24; 95% CI, 0.15-0.39; P < .001). In addition, 63% of patients treated by catheter ablation were free of any recurrent atrial arrhythmia vs 17% of patients treated with ADT (HR, 0.29; 95% CI, 0.18-0.45; P < .001).

Place holder to copy figure label and caption
Figure 2. Kaplan-Meier Curves of Time to Protocol-Defined Treatment Failure, Recurrence of Symptomatic Atrial Arrhythmia, and Recurrence of Any Atrial Arrhythmia by Treatment Group
Graphic Jump Location

HR indicates hazard ratio; CI, confidence interval.

In multivariable Cox regression modeling, the only statistically significant factor in predicting failure was treatment group, with HRs as indicated above.

In the catheter ablation group, only 5 of 67 patients classified as protocol-defined successes were taking previously ineffective class I or III antiarrhythmic drugs during the last 6 months of the effectiveness evaluation period. In the ADT group, of the 47 patients that had protocol-defined treatment failures, 36 subsequently underwent catheter ablation. For these 36 patients, the mean time to undergo ablation was 3.9 (95% CI, 3.1-4.6) months from the onset of the effectiveness evaluation period.

Major Adverse Events

Thirty-day major treatment-related adverse events occurred in 5 patients (1 pericardial effusion, 1 pulmonary edema, 1 pneumonia, 1 vascular complication, and 1 heart failure) in the catheter ablation group (5/103 [4.9%]) and 5 patients (2 with life-threatening arrhythmias and 3 with disabling drug intolerance requiring discontinuation) in the ADT group (5/57 [8.8%]). One patient in the catheter ablation group who had undergone PV isolation alone died 284 days after the procedure due to acute myocardial infarction deemed unrelated to the procedure.

Quality of Life

Baseline QOL measures were similar between treatment groups (Table 1). After the initial 3 months of the effectiveness evaluation period, mean SF-36 physical and SF-36 mental summary scores were significantly higher compared with those scores in patients treated with ADT, in whom scores changed minimally (Table 2). Patients in the catheter ablation group also reported significantly lower (better) mean symptom frequency and severity scores at 3 months. In the catheter ablation group, the improvement in SF-36 scores and decrease in symptom frequency and severity persisted without significant change at the 6- and 9-month QOL assessments. In the ADT group, crossover to ablation after 3 months resulted in progressively fewer patients still receiving drug therapy, precluding meaningful statistical comparisons.

Table Graphic Jump LocationTable 2. Quality of Life Assessment With Change From Baseline to 3 Months

Our multicenter, prospective, randomized study demonstrates that in patients with frequent symptomatic paroxysmal AF unresponsive to initial drug therapy (including ≥1 type I or III antiarrhythmic drug in 84% of patients), radiofrequency catheter ablation resulted in significantly better outcomes vs continued attempts at rhythm control with alternative drug therapy. These outcomes included a substantial reduction in the risk of recurrent atrial arrhythmias and clinically meaningful improvement in symptoms and QOL.

These data strongly support the use of catheter ablation in patients with paroxysmal AF who do not respond to initial ADT. In patients with paroxysmal or short-duration persistent AF who have had limited prior drug exposure, 20% to 40% of patients treated with class I drugs or sotalol and 60% to 70% of patients treated with amiodarone have no recurrence of AF at 1 year.911 However, failure of prior ADT (due to either recurrence or intolerance) has previously been shown to predict failure of subsequent attempts at pharmacologic rhythm control, irrespective of the specific antiarrhythmic drug.22 This latter observation is consistent with the results of our study and previously reported randomized trials that required at least 1 prior drug failure for study entry 1416; in these trials, treatment with alternative “new” antiarrhythmic drugs, including amiodarone, resulted in prevention of AF recurrence in only 9% to 23% of patients at 1 year. These data confirm that the efficacy of drug therapy for rhythm control may be considerably lower following previously failed drug trials compared with outcomes in patients not previously exposed to antiarrhythmic drugs.

In this study, both scheduled and symptom-driven transtelephonic monitoring and electrocardiogram recording were used to identify recurrences during follow-up. Ablation was associated with elimination of symptomatic atrial arrhythmia in 70% of patients, and elimination of any atrial arrhythmia irrespective of symptoms in 63% of patients at 1 year. The latter end point has been recommended by the Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society Consensus Document for standardized reporting of clinical trial outcomes.12 In prior randomized trials of catheter ablation vs ADT for paroxysmal AF, 1 year freedom from recurrent AF was reported in 56% to 89% of patients treated by catheter ablation.1416 This range of outcomes may reflect differences in patient selection, intensity of rhythm monitoring and auditing during follow-up, end points, and procedural technique. The results of this study predominantly reflect outcome after a single procedure (mean, 1.1 procedures per patient), similar to some,14,15 but not all,16 previous trials.

In patients with paroxysmal AF, elimination or amelioration of symptoms is a major driving force for therapy. A single self-limited recurrence of atrial arrhythmia following therapy may be an overly stringent criterion for failure. Assessment of total AF burden throughout follow-up by extended monitoring, while potentially the optimal end point, is technically impractical, costly, and poorly tolerated by most patients.23 In our study, catheter ablation therapy was associated with an early and sustained reduction in symptom frequency and severity, and a parallel early and sustained improvement in QOL scores. In contrast, these indices demonstrated little change over time in patients treated with ADT. The superiority of catheter ablation in this regard may be multifactorial, reflecting both the absence of adverse drug effects as well as improved rhythm control.

Catheter ablation was associated with a favorable safety profile in this study. Major adverse events have been reported in up to 6% of patients undergoing AF ablation, including thromboembolic events, atrialesophageal fistula, cardiac perforation, phrenic nerve paralysis, and death.1216,24 None of these more serious complications occurred in our study. Although use of open irrigation catheters has been reported to reduce the risk of thrombus formation at the electrode-tissue interface,25 it is unclear whether this factor alone was responsible for the absence of thromboembolic events in this study. Major adverse events or drug intolerance requiring early withdrawal of the assigned drug occurred in approximately 10% of study patients, which is comparable with other studies.

Our study has several limitations. Although the trial encompassed a broad and diverse range of ablation practices, participating investigators had considerable experience in AF ablation. Outcomes at less experienced centers or with other ablation technologies or catheters may differ. A variety of additional ablation techniques were added to the PV isolation procedure. The impact of these techniques on outcome could not be determined based on study design. The effectiveness of ablation may decrease with longer follow-up; however, it is likely that similar decreases in efficacy, as well as an increase in toxicity, may occur with ADT over time. Our study did not address the long-term effect of either therapy on mortality, stroke risk, heart failure, or progression of paroxysmal AF to more persistent or permanent forms. A potential benefit for ablation with respect to these end points has been suggested in previous retrospective uncontrolled studies,2628 but will be more definitively examined by upcoming large-scale clinical trials, such as Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA NCT00911508). In addition, study patients were relatively young with a lower incidence of cardiovascular comorbidity compared with the general population of patients with paroxysmal AF. Patients with significant left ventricular dysfunction, more persistent forms of AF, and advanced degrees of heart failure were excluded. The results of our study cannot be extrapolated to these latter populations.

Our multicenter randomized trial demonstrates the superiority of catheter ablation over ADT in the treatment of patients with paroxysmal AF who did not respond to 1 or more drugs. Catheter ablation provided significantly better rhythm control and improved QOL with a favorable safety profile. These findings argue for early use of catheter ablation therapy in patients with paroxysmal AF unresponsive to initial attempts with pharmacologic control.

Corresponding Author: David J. Wilber, MD, Cardiovascular Institute, Department of Medicine, Loyola University Medical Center, 2160 S First Ave, Bldg 110, Room 6232, Maywood, IL 60153 (dwilber@lumc.edu).

Author Contributions: Dr Wilber had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Wilber, Pappone, Natale, Calkins, Vinekar, Liu, S. Berry, D. Berry.

Acquisition of data: Wilber, Pappone, Neuzil, De Paola, Marchlinski, Macle, Daoud, Hall, Reddy, Augello, Reynolds.

Analysis and interpretation of data: Wilber, Pappone, Marchlinski, Calkins, Augello, Reynolds, Vinekar, Liu, S. Berry, D. Berry.

Drafting of the manuscript: Wilber, Natale, Hall, Vinekar, Liu.

Critical revision of the manuscript for important intellectual content: Wilber, Pappone, Neuzil, De Paola, Marchlinski, Natale, Macle, Daoud, Calkins, Reddy, Augello, Reynolds, Liu, S. Berry, D. Berry.

Statistical analysis: Marchlinski, Calkins, Reynolds, Liu, S. Berry, D. Berry.

Administrative, technical, or material support: Wilber, Pappone, Neuzil, Marchlinski, Reddy, Augello, Vinekar.

Study supervision: Wilber, Pappone, Marchlinski, Natale, Daoud.

Financial Disclosures: Dr Wilber reported receiving grants from Biosense Webster, Boston Scientific, Medtronic, and St Jude Medical; consulting fees from Biosense Webster, Medtronic, and Sanofi-Aventis; honoraria from Biosense Webster, Boston Scientific, Medtronic, and St Jude Medical; and royalties from Blackwell/Futura. Dr Pappone reported receiving grants and consulting fees from St Jude Medical and Johnson & Johnson, and honorarium from Biosense Webster. Dr Neuzil reported receiving grants from Biosense Webster, Cardiofocus, Cyrocath Technologies, Hansen Medical, NIH BARI 2D, and St Jude Medical; consulting fees from Stereotaxis; and honorarium from Biosense Webster. Dr De Paola reported receiving a grant from Bristol-Myers Squibb. Dr Marchlinski reported receiving grants and honoraria from Biosense Webster, Boston Scientific, and St Jude Medical; consulting fees from Biosense Webster, Boston Scientific, GE Healthcare, Medtronic, and St Jude Medical; and speakers' bureau fees from Biosense Webster. Dr Natale reported receiving grants from Biosense Webster and St Jude Medical, and speakers' bureau fees from Biosense Webster, Boston Scientific, Medtronic, and St Jude Medical. Dr Macle reported receiving consulting fees and honorarium from Biosense Webster. Dr Daoud reported receiving consulting fees from BARD and Biosense Webster, and honorarium from Biosense Webster. Dr Calkins reported receiving consulting fees from Ablation Frontiers, Atricure, BARD, Biosense Webster, Boston Scientific, CryoCor, CyberHeart, Medtronic, ProRhythm, Sanofi-Aventis, and TASER International; a grant and honorarium from Biosense Webster; speakers' bureau fees from Atricure, BARD, Biosense Webster, Boston Scientific, Medtronic, and Reliant; and fellowship fees from BARD, Boston Scientific, and Medtronic. Dr Hall reported receiving consulting fees from Biosense Webster. Dr Reddy reported receiving grants from Atritech, Boston Scientific, Biosense Webster, Cardiofocus, CryoCath Technologies, Endosense Hansen Medical, St Jude Medical, and Stereotaxis; consulting fees from Biosense Webster and St Jude Medical; and honoraria from Boston Scientific, Biosense Webster, Medtronic, and St Jude Medical. Dr Augello reported receiving honoraria from BARD, Biosense Webster, and St Jude Medical. Dr Reynolds reported receiving consulting fees from Biosense Webster, Cardiome Pharma Corp, and Sanofi-Aventis. Mr Vinekar and Ms Liu are employees of Biosense Webster. Drs S. Berry and D. Berry reported receiving consulting fees from Biosense Webster, Veridex LLC, Boston Scientific, Endologix, R.R. Bard, W.L. Gore, Medtronic, Bristol-Myers Squibb, Pfizer, and Teva Pharmaceuticals.

Funding/Support: This study was funded by Biosense Webster, who provided the catheters used.

Role of the Sponsor: The sponsor designed the study protocol in collaboration with the Food and Drug Administration (FDA) and participating investigators. The study was intended to support market approval of the NaviStar ThermoCool RF ablation catheter, which was manufactured by the sponsor. The sponsor had the overall responsibility for the conduct of the study, including assurance that the study met the regulatory requirements of the FDA. The sponsor's general duties consisted of submitting the Investigational Device Exemption application to the FDA, obtaining FDA and institutional review board approvals before shipping the devices, approval of the investigators, ensuring proper clinical site monitoring, and ensuring patient informed consent was obtained. The sponsor was responsible for providing quality data that satisfied federal regulations and informing proper authorities of serious unanticipated adverse events and deviations from the protocol, and for training all participating investigators on the study device and protocol and monitoring the study for data integrity throughout the duration of the investigation. In addition, the sponsor was responsible for data collection and basic data analysis. The sponsor participated in additional data analysis, data interpretation, and the drafting of the manuscript in conjunction with the principal and other investigators, as well as the decision to submit the manuscript for publication.

Independent Statistical Analysis: All efficacy and primary safety results and conclusions presented in this manuscript have been confirmed by an independent statistical review and analysis performed by Joe Massaro, PhD (Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, and Senior Biostatistical Consultant, Harvard Clinical Research Institute [HCRI], Boston, Massachusetts). Dr Massaro was provided the raw SAS data sets, analysis SAS data sets, the study protocol containing a statistical analytical plan, a blank copy of the study case report forms, and the original version of the manuscript by the authors/sponsor of the trial. Overall, Dr Massaro was in agreement with the statistical methods used in the manuscript and independently verified the primary and secondary efficacy results and conclusions presented in the final manuscript. Based on Dr Massaro's analysis, the final manuscript also included more details on the multiple imputation approach and a “worst case” approach to the frequentist analysis. Dr Massaro was compensated by the authors/sponsor for his independent statistical review through the HCRI, a nonprofit academic research organization.

The ThermoCool AF Trial Investigators:Principal Investigator: David Wilber (Loyola University Medical Center, Maywood, Illinois); co-investigators: Joseph Akar, Peter Santucci, M. Schneck; study-coordinator: Cynthia Finn. Clinical Centers:Hospital San Raffaele, Milan, Italy: Carlo Pappone (principal investigator), Giuseppe Augello, Simone Sala; Na Homolce Hospital, Prague, Czech Republic: Petr Neuzil (principal investigator), Vivek Reddy, Liz Coling, Mirka Kanova, Stepan Kralovec, Andreas Kruger, Jindrich Kupec, Jan Petru, Lucie Sediva, Milena Sidova, Jan Skoda, Milos Taborsky; Hospital São Paulo, São Paulo, Brazil: Angelo de Paola (principal investigator), Raquel de Jesus Pires Brito, Paulo Alexandre da Costa, Charles Dalegrave, Cristiano Dietrich, Carlos Romerio Costa Ferro, Veruska Hernandes, Stevie Jorge Horbach; Hospital of the University of Pennsylvania, Philadelphia: Francis Marchlinski (principal investigator), Rupa Bala, Joshua Cooper, Sanjay Dixit, Fermin Garcia, Edward Gerstenfeld, Mary Gnap, Henry Hsia, Tony Killian, David Lin, Andrea Russo, Gerilyn Schott, Ralph Verdino, Erica Zado; Cleveland Clinic Foundation, Cleveland, Ohio: Andrea Natale (principal investigator), Oussama Wazni, Mandeep Bhargava, Mauricio Arruda, J. David Burkhardt, Mina Chung, Jean Cross, Thomas Dressing, Kathy Elliott, Christina Fariello, Lon W. Castle, Jennifer E. Cummings, Donald Holmes, Frederick J. Jaeger Jr, Mark Jarosz, Mohamed Kanj, Sidney Koepp, David O. Martin, Nassir Marrouche, John Mays, Juliet Pryce, Raquel Rozich, Walid Saliba, Robert Schweikert, J. Michael Sullivan, Denise K. Sweeney, Terence Semenec, Stephanie Spencer, Patrick J. Tchou, Bruce Wilkoff; Montreal Heart Institute, Montreal, Quebec, Canada: Laurent Macle (principal investigator), Mariano Badra, Miguel Barrero, Ghislaine Bertrand, Ramon Brugada, Helene Creo, Diane David, Fabrice Demoniere, Marc Dubuc, Frederic Dumont, Pierre Gagne, Peter Guerra, Grigorios Katsouras, Paul Khairy, Kristina Lemola, Raoi Mansour, Anna Proietti, Lena Rivard, Jean-Francois Roux, Denis Roy, Lanthier Sylvain, Mario Talajic, Bernard Thibault; Midwest Cardiology, Columbus, Ohio: Emile Daoud (principal investigator), Ralph Augostini, Rose Chumita, Georgia Dawson, John Hummel, Steven Kalbfleisch; Ohio State University, Columbus: Emile Daoud (principal investigator), Ralph Augostini, Jennifer Bremer, Rose Chumita, Georgia Dawson, Kathryn Crow, John Hummel, Steven Kalbfleisch, Julie Ryan, Raul Weiss; Johns Hopkins University, Baltimore, Maryland: Hugh Calkins (principal investigator), Kathleen Avara, Ronald Berger, Cynthia Hawes, Charles Henrickson, Joseph Marine, Elizabeth Robinson, Gina Robinson, Janice Stack; University of Rochester Medical Center, Rochester, New York: Burr Hall (principal investigator), James Daubert, David Huang, Coleen Patterson, Kathryn Pyykkonen, Spencer Rosero, Janice Schrack, Carol Yeager; Arrhythmia Management, Plano, Texas: Brian Deville, Tara Weaver, Dustin Williams, Tina Worley; Marin General Hospital, Greenbae, California: Steven Hao, Linda Bartek, Salwa Beheiry, Eric Bernier, Jeremy Carnam, Richard Hongo, Gina Im, Jan Voskyul, Darla Watanabe, Raul Weiss; Arizona Arrhythmia Consultants, Scottsdale: Vijendra Swarup, Nicholas Arroyo, Marwan Bahu, Gayle Bodner, Renzo Cataldo, Nicole Ellingson, Peeyush Khanna, Angela Krebsbach, Thomas Mattioni, Ami Ning, David Riggio, Sara Scrivano, Drory Tendler, Claudia Williams, Bianca Vandermate, Lori Fausett; St Luke's Roosevelt Hospital, New York, New York: Jonathan Steinberg, Aysha Arshad, Delia Cotiga, Frederick Ehlert, Robin Knox, Walter Pierce; Inova Fairfax Hospital, Fairfax, Virginia: Ted Friehling, Margaret H. (Schenck) Bell, Marie Blake, Andrea Doctor, Sarfraz A. K. Durrani, Albert A. Del Negro, David A. Strouse, Marc H. Wish; Florida Hospital, Orlando: Scott Pollack, Leann Goodwin, Shannon Harrison, George Monir, Carol Stastny; Lahey Clinic, Burlington, Massachusetts: Roy M. John, Jean M. Byrne, Bruce G. Hook, David T. Martin, Gregory F. Michaud, Florence M. Parrella; Medical University of South Carolina, Charleston: Marcus Wharton, Elizabeth Clarke, Mariann Schultz.

Additional Contributions: We thank Albert Waldo, MD (the Walter H. Pritchard Professor of Cardiology, University Hospitals Case Medical Center, Cleveland, Ohio), for chairing the Clinical Events Committee; and Byron Allen, MD (Department of Cardiology, University of California, Irvine), for adjudicating all electrocardiographic data from the TTM transmissions. Dr Allen was compensated for his efforts by Biosense Webster. We also express our appreciation to the following affiliates from Biosense Webster, who were compensated for their efforts, in the design and execution of this study: Marcia Yaross, PhD, Brenda Aker, Robert Stagg, PhD, Kendra Lan Franco, Don Nguyen, Cheyi Lin, MS, and Brian Ramos, MS.

Fuster V, Rydén LE, Cannom DS,  et al.  ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: executive summary: 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.  J Am Coll Cardiol. 2006;48(4):854-906
PubMed   |  Link to Article
Wang TJ, Larson MG, Levy D,  et al.  Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality.  Circulation. 2003;107(23):2920-2925
PubMed   |  Link to Article
Benjamin EJ, Wolf PA, D’Agostino RB,  et al.  Impact of atrial fibrillation on the risk of death.  Circulation. 1998;98(10):946-952
PubMed   |  Link to Article
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):476-484
PubMed   |  Link to Article
Hamer ME, Blumenthal JA, McCarthy EA,  et al.  Quality-of-life assessment in patients with paroxysmal atrial fibrillation or paroxysmal superventricular tachycardia.  Am J Cardiol. 1994;74(8):826-829
PubMed   |  Link to Article
Singh SN, Tang XC, Singh BN,  et al.  Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation.  J Am Coll Cardiol. 2006;48(4):721-730
PubMed   |  Link to Article
Dorian P, Paquette M, Newman D,  et al.  Quality of life improves with treatment in the Canadian Trial of Atrial Fibrillation.  Am Heart J. 2002;143(6):984-990
PubMed   |  Link to Article
Reynolds MR, Essebag V, Zimetbaum P, Cohen DJ. Healthcare resource utilization and costs associated with recurrent episodes of atrial fibrillation.  J Cardiovasc Electrophysiol. 2007;18(6):628-633
PubMed   |  Link to Article
Roy D, Talajic M, Dorian P,  et al.  Amiodarone to prevent recurrence of atrial fibrillation.  N Engl J Med. 2000;342(13):913-920
PubMed   |  Link to Article
AFFIRM First Antiarrhythmic Drug Substudy Investigators.  Maintenance of sinus rhythm in patients with atrial fibrillation.  J Am Coll Cardiol. 2003;42(1):20-29
PubMed   |  Link to Article
Singh BN, Singh SN, Reda DJ,  et al.  Amiodarone versus sotalol for atrial fibrillation.  N Engl J Med. 2005;352(18):1861-1872
PubMed   |  Link to Article
Calkins H, Brugada J, Packet DL,  et al.  HRS/EHRA/ECAS Expert Consensus Statement on catheter and surgical ablation of atrial fibrillation.  Heart Rhythm. 2007;4(6):816-861
PubMed   |  Link to Article
Wazni OM, Marrouche NF, Martin DO,  et al.  Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation.  JAMA. 2005;293(21):2634-2640
PubMed   |  Link to Article
Stabile G, Bertaglia E, Senatore G,  et al.  Catheter ablation treatment in patients with drug refractory atrial fibrillation.  Eur Heart J. 2006;27(2):216-221
PubMed   |  Link to Article
Pappone C, Augello G, Sala S,  et al.  A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation.  J Am Coll Cardiol. 2006;48(11):2340-2347
PubMed   |  Link to Article
Jaïs P, Cauchemez B, Macle L,  et al.  Catheter ablation versus antiarrhythmic drugs for atrial fibrillation.  Circulation. 2008;118(24):2498-2505
PubMed   |  Link to Article
Ware JE Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36): I, conceptual framework and item selection.  Med Care. 1992;30(6):473-483
PubMed   |  Link to Article
Bubien RS, Knotts-Dolson SM, Plumb VJ, Kay GN. Effect of radiofrequency catheter ablation on health-related quality of life and activities of daily living in patients with recurrent arrhythmias.  Circulation. 1996;94(7):1585-1591
PubMed   |  Link to Article
Berry DA. Bayesian statistics and the efficiency and ethics of clinical trials.  Stat Sci. 2004;19:175-187
Link to Article
Berry DA. Introduction to Bayesian methods III: use and interpretation of Bayesian tools in design and analysis.  Clin Trials. 2005;2(4):295-300
PubMed   |  Link to Article
Berry DA. Bayesian clinical trials.  Nat Rev Drug Discov. 2006;5(1):27-36
PubMed   |  Link to Article
Curtis AB, Seals AA, Safford RE,  et al.  Clinical factors associated with abandonment of a rate-control or rhythm-control strategy for the management of atrial fibrillation in the AFFIRM study.  Am Heart J. 2005;149(2):304-308
PubMed   |  Link to Article
Vasamreddy CR, Dalal D, Dong J,  et al.  Symptomatic and asymptomatic atrial fibrillation in patients undergoing radiofrequency catheter ablation.  J Cardiovasc Electrophysiol. 2006;17(2):134-139
PubMed   |  Link to Article
Cappato R, Calkins H, Chen SA,  et al.  Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation.  Circulation. 2005;111(9):1100-1105
PubMed   |  Link to Article
Yokoyama K, Nakagawa H, Wittkampf FH,  et al.  Comparison of electrode cooling between internal and open irrigation in radiofrequency ablation lesion depth and incidence of thrombus and steam pop.  Circulation. 2006;113(1):11-19
PubMed   |  Link to Article
Pappone C, Rosanio S, Augello G,  et al.  Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation.  J Am Coll Cardiol. 2003;42(2):185-197
PubMed   |  Link to Article
Nademanee K, Schwab MC, Kosar EM,  et al.  Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation.  J Am Coll Cardiol. 2008;51(8):843-849
PubMed   |  Link to Article
Pappone C, Radinovic A, Manguso F,  et al.  Atrial fibrillation progression and management: a 5-year prospective follow-up study.  Heart Rhythm. 2008;5(11):1501-1507
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Patient Flow Diagram
Graphic Jump Location

AF indicates atrial fibrillation.

Place holder to copy figure label and caption
Figure 2. Kaplan-Meier Curves of Time to Protocol-Defined Treatment Failure, Recurrence of Symptomatic Atrial Arrhythmia, and Recurrence of Any Atrial Arrhythmia by Treatment Group
Graphic Jump Location

HR indicates hazard ratio; CI, confidence interval.

Tables

Table Graphic Jump LocationTable 1. Baseline Patient Characteristicsa
Table Graphic Jump LocationTable 2. Quality of Life Assessment With Change From Baseline to 3 Months

References

Fuster V, Rydén LE, Cannom DS,  et al.  ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: executive summary: 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.  J Am Coll Cardiol. 2006;48(4):854-906
PubMed   |  Link to Article
Wang TJ, Larson MG, Levy D,  et al.  Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality.  Circulation. 2003;107(23):2920-2925
PubMed   |  Link to Article
Benjamin EJ, Wolf PA, D’Agostino RB,  et al.  Impact of atrial fibrillation on the risk of death.  Circulation. 1998;98(10):946-952
PubMed   |  Link to Article
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):476-484
PubMed   |  Link to Article
Hamer ME, Blumenthal JA, McCarthy EA,  et al.  Quality-of-life assessment in patients with paroxysmal atrial fibrillation or paroxysmal superventricular tachycardia.  Am J Cardiol. 1994;74(8):826-829
PubMed   |  Link to Article
Singh SN, Tang XC, Singh BN,  et al.  Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation.  J Am Coll Cardiol. 2006;48(4):721-730
PubMed   |  Link to Article
Dorian P, Paquette M, Newman D,  et al.  Quality of life improves with treatment in the Canadian Trial of Atrial Fibrillation.  Am Heart J. 2002;143(6):984-990
PubMed   |  Link to Article
Reynolds MR, Essebag V, Zimetbaum P, Cohen DJ. Healthcare resource utilization and costs associated with recurrent episodes of atrial fibrillation.  J Cardiovasc Electrophysiol. 2007;18(6):628-633
PubMed   |  Link to Article
Roy D, Talajic M, Dorian P,  et al.  Amiodarone to prevent recurrence of atrial fibrillation.  N Engl J Med. 2000;342(13):913-920
PubMed   |  Link to Article
AFFIRM First Antiarrhythmic Drug Substudy Investigators.  Maintenance of sinus rhythm in patients with atrial fibrillation.  J Am Coll Cardiol. 2003;42(1):20-29
PubMed   |  Link to Article
Singh BN, Singh SN, Reda DJ,  et al.  Amiodarone versus sotalol for atrial fibrillation.  N Engl J Med. 2005;352(18):1861-1872
PubMed   |  Link to Article
Calkins H, Brugada J, Packet DL,  et al.  HRS/EHRA/ECAS Expert Consensus Statement on catheter and surgical ablation of atrial fibrillation.  Heart Rhythm. 2007;4(6):816-861
PubMed   |  Link to Article
Wazni OM, Marrouche NF, Martin DO,  et al.  Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation.  JAMA. 2005;293(21):2634-2640
PubMed   |  Link to Article
Stabile G, Bertaglia E, Senatore G,  et al.  Catheter ablation treatment in patients with drug refractory atrial fibrillation.  Eur Heart J. 2006;27(2):216-221
PubMed   |  Link to Article
Pappone C, Augello G, Sala S,  et al.  A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation.  J Am Coll Cardiol. 2006;48(11):2340-2347
PubMed   |  Link to Article
Jaïs P, Cauchemez B, Macle L,  et al.  Catheter ablation versus antiarrhythmic drugs for atrial fibrillation.  Circulation. 2008;118(24):2498-2505
PubMed   |  Link to Article
Ware JE Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36): I, conceptual framework and item selection.  Med Care. 1992;30(6):473-483
PubMed   |  Link to Article
Bubien RS, Knotts-Dolson SM, Plumb VJ, Kay GN. Effect of radiofrequency catheter ablation on health-related quality of life and activities of daily living in patients with recurrent arrhythmias.  Circulation. 1996;94(7):1585-1591
PubMed   |  Link to Article
Berry DA. Bayesian statistics and the efficiency and ethics of clinical trials.  Stat Sci. 2004;19:175-187
Link to Article
Berry DA. Introduction to Bayesian methods III: use and interpretation of Bayesian tools in design and analysis.  Clin Trials. 2005;2(4):295-300
PubMed   |  Link to Article
Berry DA. Bayesian clinical trials.  Nat Rev Drug Discov. 2006;5(1):27-36
PubMed   |  Link to Article
Curtis AB, Seals AA, Safford RE,  et al.  Clinical factors associated with abandonment of a rate-control or rhythm-control strategy for the management of atrial fibrillation in the AFFIRM study.  Am Heart J. 2005;149(2):304-308
PubMed   |  Link to Article
Vasamreddy CR, Dalal D, Dong J,  et al.  Symptomatic and asymptomatic atrial fibrillation in patients undergoing radiofrequency catheter ablation.  J Cardiovasc Electrophysiol. 2006;17(2):134-139
PubMed   |  Link to Article
Cappato R, Calkins H, Chen SA,  et al.  Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation.  Circulation. 2005;111(9):1100-1105
PubMed   |  Link to Article
Yokoyama K, Nakagawa H, Wittkampf FH,  et al.  Comparison of electrode cooling between internal and open irrigation in radiofrequency ablation lesion depth and incidence of thrombus and steam pop.  Circulation. 2006;113(1):11-19
PubMed   |  Link to Article
Pappone C, Rosanio S, Augello G,  et al.  Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation.  J Am Coll Cardiol. 2003;42(2):185-197
PubMed   |  Link to Article
Nademanee K, Schwab MC, Kosar EM,  et al.  Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation.  J Am Coll Cardiol. 2008;51(8):843-849
PubMed   |  Link to Article
Pappone C, Radinovic A, Manguso F,  et al.  Atrial fibrillation progression and management: a 5-year prospective follow-up study.  Heart Rhythm. 2008;5(11):1501-1507
PubMed   |  Link to Article
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