Context Treatment with antiarrhythmic drugs and anticoagulation is considered
first-line therapy in patients with symptomatic atrial fibrillation (AF).
Pulmonary vein isolation (PVI) with radiofrequency ablation may cure AF, obviating
the need for antiarrhythmic drugs and anticoagulation.
Objective To determine whether PVI is feasible as first-line therapy for treating
patients with symptomatic AF.
Design, Setting, and Participants A multicenter prospective randomized study conducted from December 31,
2001, to July 1, 2002, of 70 patients aged 18 to 75 years who experienced
monthly symptomatic AF episodes for at least 3 months and had not been treated
with antiarrhythmic drugs.
Intervention Patients were randomized to receive either PVI using radiofrequency
ablation (n=33) or antiarrhythmic drug treatment (n=37), with a 1-year follow-up.
Main Outcome Measures Recurrence of AF, hospitalization, and quality of life assessment.
Results Two patients in the antiarrhythmic drug treatment group and 1 patient
in the PVI group were lost to follow-up. At the end of 1-year follow-up, 22
(63%) of 35 patients who received antiarrhythmic drugs had at least 1 recurrence
of symptomatic AF compared with 4 (13%) of 32 patients who received PVI (P<.001). Hospitalization during 1-year follow-up occurred
in 19 (54%) of 35 patients in the antiarrhythmic drug group compared with
3 (9%) of 32 in the PVI group (P<.001). In the
antiarrhythmic drug group, the mean (SD) number of AF episodes decreased from
12 (7) to 6 (4), after initiating therapy (P = .01).
At 6-month follow-up, the improvement in quality of life of patients in the
PVI group was significantly better than the improvement in the antiarrhythmic
drug group in 5 subclasses of the Short-Form 36 health survey. There were
no thromboembolic events in either group. Asymptomatic mild or moderate pulmonary
vein stenosis was documented in 2 (6%) of 32 patients in the PVI group.
Conclusion Pulmonary vein isolation appears to be a feasible first-line approach
for treating patients with symptomatic AF. Larger studies are needed to confirm
its safety and efficacy.
Atrial fibrillation (AF), which affects approximately 2 million people
in the United States, is a major cause of stroke, adversely impacts quality
of life, and is associated with increased mortality.1-4 Treatment
with antiarrhythmic drugs and anticoagulation has been considered first-line
therapy in patients with symptomatic AF.3,5,6 However,
anticoagulation is suboptimal in many cases, and antiarrhythmic drugs are
frequently ineffective and have serious potential adverse effects.2,5-8 Preliminary
data from our and other laboratories suggest that pulmonary vein isolation
(PVI) may cure AF, obviating the need for antiarrhythmic drugs and anticoagulation
in many patients.9-13 However,
ablative therapy is usually considered only after drugs have failed because
catheter ablation is an invasive procedure with attendant potential risks,
including procedural stroke and pulmonary vein stenosis.10,12,14
Recently presented data from a study involving patients who had previously
not responded to antiarrhythmic drug therapy suggests that patients who received
catheter-based AF ablation had significantly less AF during follow-up than
those who received further antiarrhythmic drug therapy.15,16 In
contrast with this study, which used PVI as second-line therapy after antiarrhythmic
drug therapy had failed, our study was designed to determine if PVI is a feasible
option as first-line therapy for treating patients with symptomatic AF.
We conducted a multicenter prospective randomized pilot study. At the
time our study was initiated, there were no consistent data about the success
rates of PVI in the medical literature. Therefore, enrollment for our trial
was open for 6 months regardless of the sample size obtained during that period.
Patients were eligible to enter the study if they had experienced monthly
symptomatic AF episodes for at least 3 months. Exclusion criteria were age
younger than 18 years and older than 75 years, previous history of atrial
flutter or AF ablation, previous history of open-heart surgery, previous treatment
with antiarrhythmic drugs, and contraindication to long-term anticoagulation
treatment. Each patient signed a written informed consent after approval by
the institutional ethics and review board committees at each of the corresponding
Randomization was computer generated at the Cleveland Clinic Foundation,
Cleveland, Ohio, but actual enrollment occurred at the following centers:
San Giovanni, Rotondo, Italy (n = 21); Mestre, Venice, Italy (n = 23);
and Coburg, Coburg, Germany (n = 26). Patients were randomized to
receive either antiarrhythmic drug therapy or PVI for treatment of AF. Patients
were not randomized to a rate-control strategy because, at the time the study
was initiated, a rate-control strategy had not been shown to be as effective
as a rhythm-control strategy. Physicians providing patient care were advised
to keep patients in the same treatment group during the 1-year follow-up period.
All patients underwent 3 preenrollment 24-hour Holter monitoring studies.
The primary end point of the study was any recurrence of symptomatic
AF or asymptomatic AF lasting longer than 15 seconds during Holter or event
monitoring in the 1-year follow-up period. Secondary end points included hospitalization
rate during the 1-year follow-up and quality of life as assessed using the
Medical Outcomes Study 36-item Short-Form health survey (Short-Form 36).17 Quality of life was measured at enrollment and at
the 6-month follow-up visit.
Antiarrhythmic Drug Treatment
The physician providing patient care chose the drug used in the antiarrhythmic
drug study group. Each study center was advised to use the maximum tolerable
dose of each antiarrhythmic drug. An effort was made to use amiodarone only
after the patient failed at least 2 antiarrhythmic drugs. The initiation of
class I antiarrhythmic agents was conducted on an outpatient basis, while
class III agents were administered in-hospital. The recommended medical regimen
consisted of oral flecainide (100-150 mg) twice daily, propafenone (225-300
mg) 3 times daily, and sotalol (120-160 mg) twice daily. For patients not
already receiving warfarin, anticoagulation with warfarin was initiated and
maintained throughout the study in all patients enrolled in the antiarrhythmic
drug group with a target international normalized ratio of 2 to 3.
Patients were brought to the electrophysiologic laboratory in a fasting,
nonsedated state. A multipolar mapping catheter was placed into the coronary
sinus via the right internal jugular vein to record right atrial and coronary
sinus electrograms. The ablation catheter and circular mapping catheter were
placed via the right femoral vein to the left atrium using a double transseptal
puncture technique. In addition, PVI was performed by using phased-array intracardiac
echocardiographic monitoring with an intracardiac echocardiographic catheter
introduced to the right atrium via the left femoral vein.9,18 Intracardiac
echocardiography was used to ensure circular mapping catheter positioning,
appropriate site of energy delivery, and to guide energy titration by monitoring
microbubble formation. When a scattered microbubble pattern was observed,
energy was titrated down in 5-W increments until microbubble generation subsided.
Energy delivery was terminated immediately when a brisk shower of dense microbubbles
was observed. Radiofrequency energy was delivered by using an 8-mm tip ablation
catheter (Biosense Webster, Baldwin Park, Calif, and EP Technologies, Sunnyvale,
Calif). Intravenous heparin was administered to achieve an activated clotting
time of 350 to 400 seconds.
Radiofrequency ablation was performed wherever pulmonary vein potentials
were recorded around the pulmonary vein antra. The end point of ablation was
complete electrical disconnection of the pulmonary vein antrum from the left
atrium. This was considered achieved when no pulmonary vein potentials could
be recorded along the antrum or inside the vein by the circular mapping catheter,
or if there was electrical dissociation of the pulmonary vein from the left
atrium. At the end of the procedure, all 4 pulmonary venous antra were extensively
remapped with the circular mapping catheter to check for any persisting pulmonary
vein potentials and, if necessary, further ablation was performed to eliminate
these potentials. All 4 pulmonary veins were isolated. Neurological checks
were performed intermittently during the procedure, at the end of the procedure,
and the following day just before discharge.
Anticoagulation with warfarin was initiated on the evening of the PVI
procedure and continued for at least 3 months with a target international
normalized ratio of 2 to 3. Warfarin was continued if patients experienced
recurrence of AF or if at least 50% narrowing of a pulmonary vein was detected
by spiral computed tomographic scan 3 months postablation. In both treatment
groups, continuation of β-blocker therapy was left to the physician providing
Follow-up was scheduled at 1, 3, 6, and 12 months. A loop event-recorder,
which was worn for 1 month, was used in all patients to monitor events during
the first month and was repeated at 3 months. During the monitoring period,
patients were asked to record when they experienced symptoms and 2 to 3 times
daily, even if they were asymptomatic. Additional event-recorder monitoring
was obtained after the 3-month period for patients with recurrence of symptoms.
Patients were also monitored with a 24-hour Holter recording before discharge,
and at 3, 6, and 12 months postenrollment. In addition, patients were called
by telephone on a monthly basis. All patients in the PVI group had a spiral
computed tomographic scan after 3 months. This was repeated at 6 and 12 months,
if there was evidence of any degree of pulmonary venous narrowing.
All continuous variables are expressed as mean (SD) and were compared
using Student t test. Differences among groups of
continuous variables were determined by analysis of variance. Categorical
variables were compared by χ2 analysis
or Fisher exact test. SPSS version 11.0 (SPSS Inc, Chicago, Ill) was used
for the statistical analysis. Results with P<.05
were considered statistically significant.
For the 2-month period after enrollment, AF recurrence and hospitalizations
in both treatment groups were reported separately. This 2-month period was
used to account for AF recurrences and hospitalizations that occurred during
antiarrhythmic drug titration and to account for the fact that AF recurrence
early after PVI may be transient and does not necessarily imply failure of
PVI19; therefore, these data are reported separately
to minimize bias against the antiarrhythmic drug group of the study. However,
for descriptive purposes, we also present a Kaplan-Meier curve of AF-free
survival that includes all events and data during these 2 months.
From December 31, 2001, to July 1, 2002, 70 patients were enrolled.
Baseline characteristics of the study population are shown in Table 1 and Figure 1. Patients
were randomized to receive either PVI (n=33) or antiarrhythmic drug treatment
(n=37). The mean duration of AF symptoms and left ventricular ejection fraction
in both groups were comparable. In the group treated with PVI, 32 patients
had paroxysmal AF and 1 had persistent AF, whereas in the group treated with
antiarrhythmic drugs, 35 patients had paroxysmal AF and 2 had persistent AF.
At baseline, the 2 treatment groups were similar with respect to left atrial
size, prevalence of structural heart disease and hypertension, use of β-blocker
therapy, and quality of life as assessed by the Short-Form 36 health survey.
Events During the Initial 2 Months of Follow-up
During the initial 2 months of follow-up, 20 patients in the antiarrhythmic
drug group had recurrence of AF, which resulted in 26 hospitalizations for
direct current cardioversion and medication adjustment. In the PVI group,
9 patients had AF recurrence. There were no hospitalizations in the PVI group
during this period. No thromboembolic events occurred in either group.
Three patients (2 in the antiarrhythmic drug group and 1 in the PVI
group) did not present for follow-up and were excluded from the primary analysis.
These 3 patients were still alive based on vital statistics information available
at the time of preparation of this article. There were no repeat ablation
procedures throughout the 1-year period. The 1-year follow-up results are
shown in Table 2 and Table 3. After excluding events in the first 2 months after enrollment,
22 (63%) of 35 patients who received antiarrhythmic drugs had at least 1 recurrence
of symptomatic AF during the 1-year follow-up period compared with 4 (13%)
of 32 in the PVI group (P<.001) (Table 2). Asymptomatic AF was documented in 16% of the antiarrhythmic
drug group and in 2% of the PVI group (Table 3). There were no significant differences between patients who had
recurrence and those who did not with respect to age (mean [SD], 53  vs
54  years, P = .40), left atrial size
(4.1 [0.3] vs 4.2 [0.3] cm, P = .40), duration
of AF (5.4 [1.4] vs 5.1 [1.3] months, P = .50),
structural heart disease, left ventricular ejection fraction (54.4 [1.7] vs
53.2 [0.5], P = .50), and use of β-blockers
(59% vs 61%, P = .80). Three patients received
the initial antiarrhythmic drugs only; in 6 patients, the dose of the initial
antiarrhythmic drugs was increased; and in the remaining 16, the initial drug
was changed to an alternative drug. When combining the effect of the first
and second antiarrhythmic drugs, symptomatic AF reoccurred in 16 (46%) of
The initial antiarrhythmic drug used was flecainide in 27 patients (77%)
and sotalol in 8 patients (23%). Of the 27 patients who received flecainide,
20 experienced recurrence of symptomatic AF. Of those patients, the dosage
was increased in 5 patients and changed to a second antiarrhythmic drug in
15 patients. Two of the 8 patients who received sotalol as the initial antiarrhythmic
drug experienced recurrence of AF; amiodarone was then initiated for 1 patient
and the dose was increased in the second patient. Continuation of β-blocker
therapy was left to the physician providing care and was continued in 43%
of the PVI group and 52% of the antiarrhythmic drug group. A calcium channel
antagonist was not used in the PVI group, but was administered to 28% of patients
in the antiarrhythmic drug group.
Hospitalization during follow-up occurred in 19 (54%) of 35 patients
randomized to the antiarrhythmic drug treatment compared with 3 (9%) of 32
patients randomized to PVI (P<.001). In the PVI
group, the mean (SD) number of nonsustained AF episodes recorded per Holter
monitoring decreased from 13 (6) episodes pre-PVI to 1 (2) episodes after
the ablation procedure (P = .002). In the
antiarrhythmic drug group, the number of AF episodes decreased from 12 (7)
to 6 (4) (P = .01), after initiating the
therapy (Table 3). Figure 2 is a Kaplan-Meier curve presenting AF recurrences in both
Quality of Life Assessment
At 6-month follow-up, the improvement in quality of life of patients
in the PVI group was significantly better than the improvement in quality
of life in the antiarrhythmic drug group in 5 subclasses of the Short-Form
36 health survey (Table 4).
There were no thromboembolic events, defined as transient ischemic events,
stroke, deep vein thrombosis, or pulmonary embolism, in either treatment group.
Bleeding rates were similar in both groups. Incidence of documented bradycardia
was higher in the antiarrhythmic drug group (3 [8.6%] of 35 patients vs none
in the PVI group). Asymptomatic moderate (50%-70%) pulmonary vein stenosis
was documented in 1 (3%) of 32 patients in the PVI group affecting only 1
vein; no patient developed severe (>70%) pulmonary vein stenosis.
After the 1-year follow-up dictated by the study protocol, 4 patients
who had recurrence of AF in the PVI group underwent a second procedure. Three
of these patients have remained AF free and are not taking antiarrhythmic
drugs and 1 patient is in sinus rhythm with antiarrhythmic drug therapy. In
the antiarrhythmic drug group, 3 of the patients with recurrence developed
chronic AF. Additionally, 18 patients in the antiarrhythmic drug group underwent
PVI for AF recurrence. Of these patients, 15 are AF free and are not taking
antiarrhythmic drugs and 3 are in sinus rhythm with antiarrhythmic drug therapy.
One-year follow-up data were complete for all study participants except
for the 3 patients who did not return for follow-up. To assess the possible
effect of these missing data, we performed a sensitivity analysis assuming
a worst-case scenario in which 1 patient in the PVI group was assumed to have
AF recurrence and 2 patients in the antiarrhythmic drug group were assumed
to have remained AF free. In this case, the AF recurrence rate in the PVI
group would have occurred in 5 (15%) of 33 patients and in the antiarrhythmic
drug group, 22 (59%) of 37 patients, which is still significant (P<.001). Under a similar worst-case scenario for hospitalization,
there is little difference from the primary analysis.
This is the first randomized study to our knowledge demonstrating that
a strategy of using first-line PVI for symptomatic AF is associated with improved
clinical outcomes compared with initial antiarrhythmic drug therapy. Pulmonary
vein isolation was associated with less AF recurrence, improved quality of
life, and a lower hospitalization rate during follow-up after the initial
2 months of follow-up. During the initial 2 months of follow-up, there were
more recurrences in AF in both groups compared with the results reported at
1 year. However, events were higher in the antiarrhythmic drug group in this
period. The initial 2 month period was used to account for AF recurrences
and hospitalizations that occur during antiarrhythmic drug titration and to
account for the fact that AF recurrence early after PVI may be transient and
does not necessarily imply failure of PVI.19
Recent randomized trials2,8 have
shown that a strategy of rate control is comparable with a strategy of rhythm
control using antiarrhythmic drugs in treating many patients with AF. We did
not include a rate-control group because our study was initiated at a time
when the results of these trials were unknown. Even so, the degree to which
the results of these trials can be applied to our patient population is unclear.
Our study population mainly consisted of younger patients with highly symptomatic
AF. This population was underrepresented in recent trials,2,8 which
included mostly elderly patients with recurrent persistent AF. Elderly patients
tend to be less symptomatic than younger patients with paroxysmal AF20; therefore, a strategy limited to rate control in
younger patients with symptomatic AF may not be as effective in controlling
symptoms. In addition, the benefits of restoring sinus rhythm may be greater
in younger patients because doing so may prevent progressive atrial remodeling
that leads to chronic AF.21,22
The results of the rate-control vs rhythm-control trials might lead
to the conclusion that sinus-rhythm restoration is of comparable efficacy
with allowing patients to remain in AF with a controlled ventricular rate.
Such a conclusion is unwarranted. These studies only showed that a strategy
of rhythm control using antiarrhythmic drugs was comparable with a strategy
of rate control. A limitation of all these trials is that the rhythm-control
strategy was not efficacious. For example, in 1 trial,2 only
39% of patients randomized to the antiarrhythmic drug group were in sinus
rhythm at the end of the study. Furthermore, in an analysis of 1 study23 that evaluated predictors of mortality, sinus rhythm
was associated with a 47% reduction in the risk of death, whereas use of antiarrhythmic
drug therapy was associated with a 49% increase in mortality. This suggests
that the neutral results in the rate-control vs rhythm-control trials might
be explained by the fact that the benefits of antiarrhythmic drugs in restoring
sinus rhythm were negated by offsetting detrimental effects of antiarrhythmic
drug therapy. In theory, a therapy that restores and maintains sinus rhythm
while avoiding the deleterious effects of antiarrhythmic drugs would improve
survival. Pulmonary vein isolation may be such a therapy. In a recent observational
study involving a relatively large number of patients, Pappone et al24 reported that AF ablation was associated with significantly
lower mortality and adverse events compared with drug therapy.
In current clinical practice, ablation therapy for AF is reserved for
patients with symptoms who have failed multiple antiarrhythmic drug regimens.
The primary concern in offering an ablation procedure to treat AF as first-line
therapy is that complications from the procedure can occur. A recent worldwide
survey of more than 8000 AF ablation procedures reported an overall major
complication rate of 6%.25 However, it should
be noted that many of the complications, although serious, typically result
in only acute and not long-term morbidity. These complications include femoral
pseudoaneurysm, arteriovenous fistula, pneumothorax, hemothorax, transient
ischemic attack, and cardiac tamponade. The most serious complications resulting
in permanent disability were uncommon (death in 0.05% and stroke in 0.28%).
Significant pulmonary vein stenosis was reported in 1.3%, but this can be
treated with percutaneous interventional procedures.14,26,27 A
recently recognized complication of catheter-based AF ablation is left atrial-esophageal
fistula, which could lead to death.28-30
Contrasting the risks of PVI are the risks associated with antiarrhythmic
drug therapy, which may not be trivial. In 1 trial, antiarrhythmic drugs were
associated with a 49% increased risk of death after taking into account the
presence of sinus rhythm.23 In addition, because
antiarrhythmic drugs are frequently ineffective in maintaining sinus rhythm,
patients taking antiarrhythmic drugs may remain at risk for long-term complications
of AF, such as stroke. The balance between the acute risks of PVI vs the long-term
risks of AF is unclear.
Our study had several limitations, which included a pilot study with
a small number of relatively young patients and the ablation procedures performed
at highly specialized centers. The sample size and 1-year follow-up period
were not large enough to assess the effects of therapy on important but infrequent
outcomes, such as stroke. The long-term cure rate for the PVI procedure is
unknown. Quality of life was only assessed at baseline and 6-month follow-up.
Although many patients were receiving atrioventricular nodal blocking agents,
there was no rate-control group. Because of the potential for end-organ toxicity,
the use of amiodarone was discouraged and used infrequently. However, amiodarone
may be slightly more effective at maintaining sinus rhythm than other antiarrhythmic
drugs.31 The technique used for performing
PVI is similar but not identical to other catheter-based techniques for performing
AF ablation.25 Which ablation technique is
best is controversial. Also, techniques for performing AF ablation continue
to change as knowledge, experience, and technology advance. Additionally,
cost-effectiveness was not addressed in our study. In future studies, the
initial 2-month follow-up period would most likely be taken into account when
Based on the results of our study, we conclude that PVI is a feasible
first-line approach for the treatment of selected patients with symptomatic
AF. To further assess whether the benefits of AF ablation outweigh the inherent
risks of an invasive procedure requires a multicenter randomized trial with
a larger number of centers and patients, and longer follow-up. Until such
a study is performed, PVI should not be considered standard of care as first-line
therapy for AF. Nevertheless, the results of our study suggest that ablation
to cure AF may become the treatment of first choice in appropriately selected
patients with AF.
Corresponding Author: Andrea Natale, MD,
Department of Cardiovascular Medicine, Center for Atrial Fibrillation, Cleveland
Clinic Foundation, Desk F 15, 9500 Euclid Ave, Cleveland, OH 44195 (email@example.com).
Author Contributions: Dr Natale 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: Wazni, Marrouche,
Martin, Verma, Saliba, Schweikert, Brachmann, Gunther, Gutleben, Raviele,
Rossillo, Bonso, Natale.
Acquisition of data: Marrouche, Saliba, Bash,
Schweikert, Brachmann, Gunther, Gutleben, Pisano, Potenza, Fanelli, Raviele,
Themistoclakis, Rossillo, Bonso, Natale.
Analysis and interpretation of data: Marrouche,
Drafting of the manuscript: Wazni, Martin,
Critical revision of the manuscript for important
intellectual content: Marrouche, Verma, Bhargava, Saliba, Bash, Schweikert,
Brachmann, Gunther, Gutleben, Pisano, Potenza, Fanelli, Raviele, Themistoclakis,
Rossillo, Bonso, Natale.
Statistical analysis: Wazni, Marrouche, Martin,
Verma, Brachmann, Gunther, Gutleben, Pisano, Potenza, Raviele, Themistoclakis,
Rossillo, Bonso, Natale.
Obtained funding: Natale.
Administrative, technical, or material support:
Marrouche, Saliba, Bash, Pisano, Fanelli, Natale.
Study supervision: Marrouche, Martin, Bhargava,
Saliba, Schweikert, Brachmann, Gunther, Gutleben, Potenza, Fanelli, Raviele,
Themistoclakis, Rossillo, Bonso, Natale.
Financial Disclosures: None reported.
Funding/Support: This study was supported in
part by an unrestricted educational grant from Acuson, a division of Siemens
Role of the Sponsor: Acuson did not participate
in the design and conduct of the study, in the collection, analysis, and interpretation
of the data, or in the preparation, review, or approval of the manuscript.
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