Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01439386 |
| Other study ID # |
TCAI_APPROVAL |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
September 21, 2011 |
| Last updated |
October 17, 2017 |
| Start date |
September 2011 |
| Est. completion date |
July 2016 |
Study information
| Verified date |
October 2017 |
| Source |
Texas Cardiac Arrhythmia Research Foundation |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This prospective, multi-center, single blinded study aims to compare the influence of two
different catheter ablation strategies, on long-term ablation outcome in terms of AF
recurrence and quality of life (QoL) in patients presenting with coexistent AF and AFL. The
two strategies to be evaluated are 1) the ablation of paroxysmal atrial fibrillation (PAF)
with or without flutter (AFL) ablation (AF ± AFL) versus 2) AFL ablation alone.
Description:
Specific Aim: This prospective single blinded study aims to compare the influence of two
different catheter ablation strategies, on long-term ablation outcome in terms of AF
recurrence and quality of life (QoL) in patients presenting with coexistent AF and AFL. The
two strategies to be evaluated are 1) the ablation of paroxysmal atrial fibrillation (PAF)
with or without flutter (AFL) ablation (AF ± AFL) versus 2) AFL ablation alone.
Hypothesis: Ablation of AF ± AFL results in better long-term procedure outcome than
AFL-ablation alone in patients with a documented history of AF and AFL.
Background: Coexistence of AF and AFL is commonly encountered in clinical practice. Patients
with these arrhythmias experience symptoms such as palpitation which is often described as a
sudden irregular fluttering sensation in the chest, dyspnea, fatigue, dizziness and fainting
attacks. These symptoms make the patients anxious and tired and seriously compromise their
QoL (1).
Radiofrequency catheter ablation (RFCA) has emerged as the best therapeutic option in
drug-refractory AF cases and often used as a first-line therapy in AFL (2). Several studies
have demonstrated significant improvement in QoL following catheter ablation (CA) when
patients have either AF or AFL (3-9). However, very little is known about the impact of CA on
QoL in patients presenting with coexistent AF and AFL.
No standard treatment guidelines exist for coexistent AF and AFL. Determining the best
ablative approach for this type of patient remains a challenge. Roithinger et al (10)
postulated that the mechanism of AFL in patients presenting with both arrhythmias could be
organization of AF to AFL. However, it is not always possible to determine which is the
predominate arrhythmia. In some cases, AFL ablation can eliminate AF and AFL, and is a less
extensive procedure than AF ablation. As the two arrhythmias are inter-twined, it is possible
that AFL ablation alone may be sufficient to cure both arrhythmias. Should an AF ablation be
required at a later date, there is no supportive data suggesting that the second procedure is
associated with additional complications. Therefore, performing an AFL ablation alone does
not expose the patient to any unwarranted risk. (11) Several published studies have reported
on a variety of ablation strategies for different types of AF, to include paroxysmal,
persistent and long standing persistent, with variable results on AF recurrence. (12-16)
Compared to previous studies, the scope of the APPROVAL study is narrowed to include patients
with AF falling into the 'paroxysmal' category.
In a randomized trial, Wazni et al compared the outcome in PV disconnection alone for AF
versus PV disconnection plus cavotricuspid isthmus ablation for AFL. They concluded that in
patients with coexistent AF and AFL, comparable long-term outcome in terms of arrhythmia-free
existence was observed among patients undergoing either AF ablation only or AF+AFL ablation.
Performance or lack of performance of AFL ablation along with AF ablation, did not
significantly affect the long-term outcome. Therefore, the APPROVAL study allows group 1
patients to undergo the AFL ablation or not undergo the AFL ablation based on physician
discretion, with the belief that an AFL ablation in this setting will not affect the outcome.
Ablation of AFL for the treatment of AF / AFL, followed by anti-arrhythmic drug (AAD) therapy
for 3 months is a commonly used approach. QoL assessment focuses on the physical, social and
emotional consequences of illness. The subjective perception of 'illness intrusiveness', and
how the disease burden affects the general well-being are of great interest in this
population.(17) Several standardized questionnaires are available to quantitatively assess
QoL. In this study, 4 of those will be used, namely Medical Outcome Study Short Form-36
(SF-36), Hospital Anxiety and Depression Score (HAD), Beck Depression Inventory (BDI) and
State-Trait Anxiety Inventory (STAI).
Study Objective:
To compare long-term procedure-outcome, following AF with or without AFL ablation versus AFL
ablation alone, in patients presenting with both PAF and AFL.
Study Design:
This prospective, single blind randomized study would enroll 86 patients presenting with
documented symptomatic PAF and typical isthmus dependent AFL that are scheduled to undergo
catheter ablation.
Endpoints:
Primary: Recurrence of atrial arrhythmia: any episode of AF/AT longer than 30 sec will be
considered as a recurrence. Episodes that occur during the first 3 months after the procedure
(blanking period) will not be considered as recurrence.
Secondary: Change in QoL score from baseline
Study Procedures:
Baseline:
Consenting patients would be randomly assigned to either AF±AFL ablation (group 1) or AFL
ablation only (group 2). In group 1, AF ablation will be performed in all cases. In addition,
the physician will also perform an AFL ablation if any one of the following criteria are met:
- The patient demonstrates spontaneous right-sided isthmus-dependent flutter upon arrival
for the ablation procedure
- Right-sided isthmus-dependent flutter is inducible anytime during the ablation procedure
- The patient spontaneous converts to right-sided isthmus-dependent flutter anytime during
the ablation procedure
In group 2, all patients will undergo ablation of AFL only. Because QoL could be affected by
a placebo effect of the procedure, the patients will be blinded to their group assignment.
Baseline QoL surveys will be collected for all patients prior to their ablation.
Ablation Procedure:
Standard mapping and ablation techniques will be conducted at the discretion of the
physician, with RF lesions administered at the location determined by the randomization
assignment. This includes pulmonary vein isolation (PVI) and ablation of extra-pulmonary
triggers detected by standard mapping procedure for AF (18) and cavo-tricuspid isthmus
ablation for atrial flutter (2). The endpoint of the procedure is defined as the termination
or non-inducibility of AF or AFL.
Follow-up:
Study follow-up will last for one year. Following ablation, patients will be discharged on
their previously ineffective AADs which will be continued for 90 days (blanking period). The
blanking period allows time for the inflammatory process to subside. AADs will be
discontinued after the blanking period for all patients. If a patient suffers a recurrence of
an atrial arrhythmia, the primary end point will be met and the AAD therapy may be
administered at the discretion of the physician.
Patients will use an event recorder for 5 months after ablation, and will be asked to
transmit their rhythm every time they experience symptoms compatible with arrhythmias, and at
least twice a week even if asymptomatic. Any episode of AF/AT longer than 30 sec after the 3
month blanking period will be considered as a recurrence.
A 7 day Holter monitor will be worn at the 3, 6, 9 and 12 month time points after the
procedure.
QoL surveys will be self-administered at the 3 and 12-month time points.
Risk Analysis:
This study does not pose any additional risk to the patient. The risks are the same for both
groups and are the same as those for a standard atrial fib or flutter ablation. Per standard
of care, ablation procedures are not scheduled for pregnant patients. A pregnancy test is
routinely performed prior to the ablation procedure to confirm that the patient is not
pregnant.
There is no risk associated with study withdraw since the study is collecting only routine
data, and there are no protocol specific follow-up procedures.
Probability of requiring a repeat ablation:
The probability of arrhythmia recurrence (AF and/or AFL) after AF ± AFL ablation was reported
to be between 52% [Scharf et al (19)] to 58% [Husser et al (20)]. According to Scharf et al,
the recurrence of typical flutter alone after AF ± AFL ablation was 12%.
The recurrence of typical flutter among patients undergoing AFL ablation alone, has been
reported to be 11% [Bertaglia et al (21)] to 12% [Luca CT et al (22)]. However, the
cumulative probability of recurrence of combined AF and AFL in this AFL ablation only
population has been 50% at 2 years and 58% at 3 years.(21) Therefore, the overall probability
of going for a redo ablation after AF ± AFL ablation compared to that of AFL ablation alone
is not be significantly different (52% vs 50%, p>0.5).
Regarding risks associated with a repeat procedure, no additional identifiable risks have
been reported for patients undergoing a second procedure (19) (23). However, potential study
subjects will be advised that standard procedural risks would be present with a repeat
procedure. These include cardiac tamponade CVA, esophageal fistula, pulmonary vein stenosis,
bleeding, myocardial infarction, death and injury to the cardiac conduction system.
Benefits: The subject may not incur any benefit by participating in this study.
Statistical Methodology:
Sample size determination and power analysis:
Reported success rates from previous studies were used to determine the minimal difference of
outcome (effect size). Published results indicate that the observed success rate (freedom
from arrhythmia) has been 65% in group 1 and 30% in group 2. The sample size necessary to
detect an effect size of 35% for the primary outcome was determined using alpha = 0.05 and
power = 0.80 (beta= 0.20). The minimum required sample size (two-sample parallel design test
for superiority model) for each group came out to be 43 patients.
Sampling Plan:
A central database will be created which will hold all the eligible subjects. Permuted block
randomization method will be used for treatment allocation.
Analysis Plan:
The continuous variables will be reported as mean ± standard deviation (SD). The categorical
variables will be reported as number of cases (n) and percentage. The bivariate analyses for
comparing the characteristics across the two study groups will be performed using Student's
t-test for continuous variables and chi-square test for categorical variables. A stratified
sub-analysis will be performed for assessing outcome across AF and AF+CTI groups with a
multivariable risk-adjusted model. A two-tailed p value of <0.05 is considered statistically
significant. Time series analysis will be performed, using Kaplan Meier test and multivariate
analysis with Cox proportional-hazards model, to compare recurrence at follow-up. SAS 9.2
(SAS Institute Inc., Cary, NC) will be used for statistical analysis. Statistical testing
will compare Group 1 & 2, as well as provide a subanalysis of Group 1 (with and without AFL
ablation).
