The Substrate and Intervention Mechanisms for Persistent Atrial Fibrillation Trial
| Status: | Terminated |
|---|---|
| Conditions: | Atrial Fibrillation |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 1/6/2018 |
| Start Date: | April 2016 |
| End Date: | October 2017 |
The Substrate and Intervention Mechanisms for Persistent Atrial Fibrillation (SIMPle AF) Trial
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with increasing
morbidity and mortality. A catheter-based AF ablation technique that isolates pulmonary veins
(PV) from the left atrium has been established to disrupt AF. Despite significant
development, AF ablation with pulmonary vein isolation (PVI) is reported to have a success
rate of 40-80% in various AF populations.
Persistent AF appears to be more reliant upon fibroblast proliferation and myocyte-fibroblast
coupling than paroxysmal AF with obvious implications on its management. Despite the
knowledge that fibrotic substrate is responsible for the perpetuation of persistent AF,
several ablation techniques targeting these extra-pulmonary veins sites have failed to prove
an additional benefit to PVI alone. Nevertheless, two recently developed technologies, aimed
at detecting AF substrate with high precision, seem to constitute a potential breakthrough in
the management of persistent AF. On one hand, late gadolinium-enhanced MRI (LGE-MRI) is a
well-established method to identify fibrosis in the myocardium. Recent reports from a single
center have shown that MRI-based left atrial fibrosis detection is able to predict the
outcome of the procedure. Hence, targeting lesions seen on LGE-MRI in the setting of
persistent AF is an option yet to be explored and compared to the widely adopted, yet
suboptimal, PVI. On another hand, a novel ablation method with promising results is focal
impulse and rotor modulation (FIRM). Undergoing wide sampling of the atria with
spatiotemporal and computational mapping while in AF has identified areas with stable
organized rotational electrical activity (rotors). Several studies are under way to prove the
reproducibility of rotor mapping, with more groups reporting improved rates of acute and
long-term suppression of AF with ablation of FIRM-identified rotors.
The SIMPle AF study will be a randomized clinical trial designed to test the hypothesis that
ablation tailored to the underlying substrate using either LGE-detected dense scar or rotor
anchor sites predicted by computational modeling is superior to anatomic non-tailored PVI
ablation in patients with persistent AF. For the present study, the investigators plan to
enroll a total of 30 patients.
morbidity and mortality. A catheter-based AF ablation technique that isolates pulmonary veins
(PV) from the left atrium has been established to disrupt AF. Despite significant
development, AF ablation with pulmonary vein isolation (PVI) is reported to have a success
rate of 40-80% in various AF populations.
Persistent AF appears to be more reliant upon fibroblast proliferation and myocyte-fibroblast
coupling than paroxysmal AF with obvious implications on its management. Despite the
knowledge that fibrotic substrate is responsible for the perpetuation of persistent AF,
several ablation techniques targeting these extra-pulmonary veins sites have failed to prove
an additional benefit to PVI alone. Nevertheless, two recently developed technologies, aimed
at detecting AF substrate with high precision, seem to constitute a potential breakthrough in
the management of persistent AF. On one hand, late gadolinium-enhanced MRI (LGE-MRI) is a
well-established method to identify fibrosis in the myocardium. Recent reports from a single
center have shown that MRI-based left atrial fibrosis detection is able to predict the
outcome of the procedure. Hence, targeting lesions seen on LGE-MRI in the setting of
persistent AF is an option yet to be explored and compared to the widely adopted, yet
suboptimal, PVI. On another hand, a novel ablation method with promising results is focal
impulse and rotor modulation (FIRM). Undergoing wide sampling of the atria with
spatiotemporal and computational mapping while in AF has identified areas with stable
organized rotational electrical activity (rotors). Several studies are under way to prove the
reproducibility of rotor mapping, with more groups reporting improved rates of acute and
long-term suppression of AF with ablation of FIRM-identified rotors.
The SIMPle AF study will be a randomized clinical trial designed to test the hypothesis that
ablation tailored to the underlying substrate using either LGE-detected dense scar or rotor
anchor sites predicted by computational modeling is superior to anatomic non-tailored PVI
ablation in patients with persistent AF. For the present study, the investigators plan to
enroll a total of 30 patients.
Objectives The main objective of the study is to identify the optimal ablation strategy for
suppression of persistent AF.
The secondary objectives of the study are:
- To define the local myocardial image characteristics of slow conduction AF substrates.
- To define the local myocardial structural changes post ablation that associate with AF
suppression at 1-year follow-up
- To compare cardiac remodeling and atrial function at 1-year follow-up between PVI only
and tailored catheter ablation groups
Background
Atrial fibrillation (AF) is associated with increased risk for mortality, heart failure, and
thromboembolic events, and has a worldwide prevalence of >33.5 million. Catheter ablation of
AF is evolving as an effective therapy for symptomatic AF. Recurrent AF after ablation,
however, remains a problem and has been reported to associate with the baseline extent of
left atrial (LA) late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR).
Mechanistically, persistent AF appears to be more reliant upon fibroblast proliferation and
myocyte-fibroblast coupling than paroxysmal AF, which is primarily dependent upon pulmonary
vein triggers. Therefore, the investigators hypothesize that the substrate for persistent AF
is detectable on atrial LGE-CMR and variable among patients, and that the substrate predicts
patient outcomes after anatomic non-tailored ablation, and is more likely to respond to
individually tailored ablation approaches. Two individually tailored approaches will be
studied including empiric targeting of dense LGE, confirmed on bipolar mapping to have
voltage <0.3 mV, and modeling based targeting of rotor anchor sites.
Study Design
Initially, the investigators propose prospective enrollment of 30 participants with
persistent AF. Patients presenting to the institution who meet the inclusion criteria will be
asked to participate in the study. All patients will undergo routine clinical care including
echocardiography as indicated.
All patients will undergo a LGE-MRI within 30 days prior to the ablation procedure. The
clinical purpose of the initial MRI is to define the anatomy of the heart chambers as well as
the vessels for procedure planning. For research purposes, the investigators will use this
initial clinical MRI to delineate atrial structural remodeling or fibrosis to be used during
the procedure in patients randomized to group 2 (pulmonary vein isolation + scar-based
ablation) and for later analysis in all patients.
Imaging is done at the institution and will be reviewed for quality by the study staff.
LGE-MRI sequences that do not meet quality standards for fibrosis analysis will not be
further processed and these patients will be excluded from the study. Subjects for whom
images are successfully evaluated will be randomized to the study groups.
This will be followed by block randomization in 1:1:1 format to a) pulmonary vein isolation
(PVI) only (current standard of care), b) PVI plus targeting of dense LGE sites, which are
confirmed on bipolar mapping to have voltage <0.3 mV, and c) PVI plus targeting of rotor
anchor sites predicted by modeling.
At baseline, all patients will be evaluated for their quality of life (QOL) using the
Short-form health survey (SF-36) for overall as well as AF-related impact on quality of life.
The severity of symptoms will also be tested using the European Heart Rhythm Association
(EHRA) score of atrial fibrillation. Clinical data will be stored electronically and linked
to a specific research number. Information linking de-identified data to the patients will be
stored in the locked research office, in a password-protected file. Only members of the
research team, in charge of collecting clinical information, will have access to this file.
Individual subject binders containing signed consent forms and clinical source documentation
will be labeled using study subject numbers and stored in the locked research office
mentioned previously.
A pre-ablation cardiac MRI is clinically indicated to assess baseline cardiac anatomy prior
to procedure. Routine and LGE protocols will be used to acquire MR images. All patients will
be asked to undergo a repeat LGE-MRI 12 months after the ablation. This is done for research
purposes. Renal function is routinely monitored prior to gadolinium-enhanced MRI as a
standard of clinical care.
With regards to the ablation procedure, all patients will undergo AF ablation. The procedure
consists of circumferential pulmonary vein lesions under electro-anatomical guidance using
CARTO (Biosense Webster Inc., Diamond Bar, CA). Operators will use either a 3.5mm irrigated
tip radiofrequency ablation catheter (ThermoCool Smart-Touch, Biosense Webster Inc., Diamond
Bar, CA) or a cryoballoon catheter (Arctic Front Advance, Medtronic Inc., Minneapolis, MN).
This procedure is FDA approved and will be conducted in all treatment arms according to
standard of care. However, patients in the second group will undergo additional targeting of
dense LGE sites, confirmed on bipolar mapping to have voltage <0.3 mV and patients in the
third group will undergo targeting of rotor anchor sites as predicted by computational
modeling. A detailed protocol of rotor ablation is described in the literature and shows no
added complications compared to the conventional procedure.
To prevent short-term recurrence of AF, patients will be kept on anti-arrhythmic regimen for
the first 1 to 3 months after the ablation to be discontinued thereafter in the absence of AF
recurrence, at the discretion of the treating physician. In addition, standard protocols for
anticoagulation prior to, during, and after the ablation procedure will be applied.
After the ablation, clinical follow-up visits are scheduled at 3, 6 and 12 months. Research
follow-up questionnaires and 12-lead ECG recordings will be done at the same day of the
visits. All patients will undergo rhythm monitoring to detect AF recurrence using a portable,
smart phone operated, AliveCor® Mobile ECG device.This device will be provided to the
patients at no cost after enrollment in the study.
After the procedure, follow-up will be done on a weekly basis through trans-telephonic
transmissions of ECG recordings. Periodic reminders will be sent to patients (via telephone,
email, or mail) regarding follow up transmissions in the event that a weekly transmission is
missed. In addition, study participants will be advised to provide recordings if they
experience heart-related symptoms (palpitations, shortness of breath, rapid heartbeat, chest
pain). This extensive rhythm monitoring protocol is not standard of care and is done for
research purposes. Review of the rhythm monitoring data will be performed in accordance with
current clinical guidelines. The device software and the investigators will analyze rhythm
strips and a report will be available to the research team and to the treating physician upon
his/her request. In addition, upon detection of any arrhythmia with important clinical
implications, the investigators will notify the electrophysiologist involved in the care of
the patient. The research team may contact the patient directly if prompt action is advised,
such as reporting to the local emergency room or following up with their electrophysiologist.
The rhythm monitoring protocol utilized in this study may result in unscheduled visits to the
physician. If a repeat ablation procedure is indicated, it will be scheduled according to
standards of clinical care.
Study duration and visits.
The investigators aim to complete the proposed study protocol in two years. After the
ablation, patients will be followed at 3, 6 and 12 months via in clinic visit; a 1 month and
9 month follow up will take place via remote ECG transmission. Follow-up research
questionnaires and post-ablation MRI will be scheduled to coincide with the routine clinical
visits. Hence, no additional visits will be required of research participants unless it was
not possible to schedule the MRI on the same day as clinic visits. Only then will the
investigators ask participants to present to the institution for the follow-up MRI.
Study Statistics
Based on the variable success rate of 40-80% in AF ablation, the investigators anticipate
that the study cohort of 30 patients would produce adequate sample size in all treatment arms
and be sufficient to make meaningful statistical comparison.
Comparison variables will be presented as means +/- standard deviation, and categorical
variables as numbers and percentages. Differences between treatment groups will be assessed
using the Pearson Chi-square test and the Wilcoxon rank-sum test. Survival curves for time to
event analysis will be estimated using the Kaplan-Meier method, and the differences between
the curves will be tested for significance with the log-rank statistic. Weekly event rates
will be calculated by dividing the event rate by the maximum follow-up period in each arm of
the Kaplan-Meier analysis. Hazard ratios will be calculated by univariate and multivariate
analysis using the Cox proportional-hazards regression model. When comparing MR image
characteristics as well as LA function between pre and post-ablation imaging, the Student's
t-test will be using for comparison of the means. All statistical testing will be 2-tailed.
Results will be considered statistically significant at a level of p<0.05.
suppression of persistent AF.
The secondary objectives of the study are:
- To define the local myocardial image characteristics of slow conduction AF substrates.
- To define the local myocardial structural changes post ablation that associate with AF
suppression at 1-year follow-up
- To compare cardiac remodeling and atrial function at 1-year follow-up between PVI only
and tailored catheter ablation groups
Background
Atrial fibrillation (AF) is associated with increased risk for mortality, heart failure, and
thromboembolic events, and has a worldwide prevalence of >33.5 million. Catheter ablation of
AF is evolving as an effective therapy for symptomatic AF. Recurrent AF after ablation,
however, remains a problem and has been reported to associate with the baseline extent of
left atrial (LA) late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR).
Mechanistically, persistent AF appears to be more reliant upon fibroblast proliferation and
myocyte-fibroblast coupling than paroxysmal AF, which is primarily dependent upon pulmonary
vein triggers. Therefore, the investigators hypothesize that the substrate for persistent AF
is detectable on atrial LGE-CMR and variable among patients, and that the substrate predicts
patient outcomes after anatomic non-tailored ablation, and is more likely to respond to
individually tailored ablation approaches. Two individually tailored approaches will be
studied including empiric targeting of dense LGE, confirmed on bipolar mapping to have
voltage <0.3 mV, and modeling based targeting of rotor anchor sites.
Study Design
Initially, the investigators propose prospective enrollment of 30 participants with
persistent AF. Patients presenting to the institution who meet the inclusion criteria will be
asked to participate in the study. All patients will undergo routine clinical care including
echocardiography as indicated.
All patients will undergo a LGE-MRI within 30 days prior to the ablation procedure. The
clinical purpose of the initial MRI is to define the anatomy of the heart chambers as well as
the vessels for procedure planning. For research purposes, the investigators will use this
initial clinical MRI to delineate atrial structural remodeling or fibrosis to be used during
the procedure in patients randomized to group 2 (pulmonary vein isolation + scar-based
ablation) and for later analysis in all patients.
Imaging is done at the institution and will be reviewed for quality by the study staff.
LGE-MRI sequences that do not meet quality standards for fibrosis analysis will not be
further processed and these patients will be excluded from the study. Subjects for whom
images are successfully evaluated will be randomized to the study groups.
This will be followed by block randomization in 1:1:1 format to a) pulmonary vein isolation
(PVI) only (current standard of care), b) PVI plus targeting of dense LGE sites, which are
confirmed on bipolar mapping to have voltage <0.3 mV, and c) PVI plus targeting of rotor
anchor sites predicted by modeling.
At baseline, all patients will be evaluated for their quality of life (QOL) using the
Short-form health survey (SF-36) for overall as well as AF-related impact on quality of life.
The severity of symptoms will also be tested using the European Heart Rhythm Association
(EHRA) score of atrial fibrillation. Clinical data will be stored electronically and linked
to a specific research number. Information linking de-identified data to the patients will be
stored in the locked research office, in a password-protected file. Only members of the
research team, in charge of collecting clinical information, will have access to this file.
Individual subject binders containing signed consent forms and clinical source documentation
will be labeled using study subject numbers and stored in the locked research office
mentioned previously.
A pre-ablation cardiac MRI is clinically indicated to assess baseline cardiac anatomy prior
to procedure. Routine and LGE protocols will be used to acquire MR images. All patients will
be asked to undergo a repeat LGE-MRI 12 months after the ablation. This is done for research
purposes. Renal function is routinely monitored prior to gadolinium-enhanced MRI as a
standard of clinical care.
With regards to the ablation procedure, all patients will undergo AF ablation. The procedure
consists of circumferential pulmonary vein lesions under electro-anatomical guidance using
CARTO (Biosense Webster Inc., Diamond Bar, CA). Operators will use either a 3.5mm irrigated
tip radiofrequency ablation catheter (ThermoCool Smart-Touch, Biosense Webster Inc., Diamond
Bar, CA) or a cryoballoon catheter (Arctic Front Advance, Medtronic Inc., Minneapolis, MN).
This procedure is FDA approved and will be conducted in all treatment arms according to
standard of care. However, patients in the second group will undergo additional targeting of
dense LGE sites, confirmed on bipolar mapping to have voltage <0.3 mV and patients in the
third group will undergo targeting of rotor anchor sites as predicted by computational
modeling. A detailed protocol of rotor ablation is described in the literature and shows no
added complications compared to the conventional procedure.
To prevent short-term recurrence of AF, patients will be kept on anti-arrhythmic regimen for
the first 1 to 3 months after the ablation to be discontinued thereafter in the absence of AF
recurrence, at the discretion of the treating physician. In addition, standard protocols for
anticoagulation prior to, during, and after the ablation procedure will be applied.
After the ablation, clinical follow-up visits are scheduled at 3, 6 and 12 months. Research
follow-up questionnaires and 12-lead ECG recordings will be done at the same day of the
visits. All patients will undergo rhythm monitoring to detect AF recurrence using a portable,
smart phone operated, AliveCor® Mobile ECG device.This device will be provided to the
patients at no cost after enrollment in the study.
After the procedure, follow-up will be done on a weekly basis through trans-telephonic
transmissions of ECG recordings. Periodic reminders will be sent to patients (via telephone,
email, or mail) regarding follow up transmissions in the event that a weekly transmission is
missed. In addition, study participants will be advised to provide recordings if they
experience heart-related symptoms (palpitations, shortness of breath, rapid heartbeat, chest
pain). This extensive rhythm monitoring protocol is not standard of care and is done for
research purposes. Review of the rhythm monitoring data will be performed in accordance with
current clinical guidelines. The device software and the investigators will analyze rhythm
strips and a report will be available to the research team and to the treating physician upon
his/her request. In addition, upon detection of any arrhythmia with important clinical
implications, the investigators will notify the electrophysiologist involved in the care of
the patient. The research team may contact the patient directly if prompt action is advised,
such as reporting to the local emergency room or following up with their electrophysiologist.
The rhythm monitoring protocol utilized in this study may result in unscheduled visits to the
physician. If a repeat ablation procedure is indicated, it will be scheduled according to
standards of clinical care.
Study duration and visits.
The investigators aim to complete the proposed study protocol in two years. After the
ablation, patients will be followed at 3, 6 and 12 months via in clinic visit; a 1 month and
9 month follow up will take place via remote ECG transmission. Follow-up research
questionnaires and post-ablation MRI will be scheduled to coincide with the routine clinical
visits. Hence, no additional visits will be required of research participants unless it was
not possible to schedule the MRI on the same day as clinic visits. Only then will the
investigators ask participants to present to the institution for the follow-up MRI.
Study Statistics
Based on the variable success rate of 40-80% in AF ablation, the investigators anticipate
that the study cohort of 30 patients would produce adequate sample size in all treatment arms
and be sufficient to make meaningful statistical comparison.
Comparison variables will be presented as means +/- standard deviation, and categorical
variables as numbers and percentages. Differences between treatment groups will be assessed
using the Pearson Chi-square test and the Wilcoxon rank-sum test. Survival curves for time to
event analysis will be estimated using the Kaplan-Meier method, and the differences between
the curves will be tested for significance with the log-rank statistic. Weekly event rates
will be calculated by dividing the event rate by the maximum follow-up period in each arm of
the Kaplan-Meier analysis. Hazard ratios will be calculated by univariate and multivariate
analysis using the Cox proportional-hazards regression model. When comparing MR image
characteristics as well as LA function between pre and post-ablation imaging, the Student's
t-test will be using for comparison of the means. All statistical testing will be 2-tailed.
Results will be considered statistically significant at a level of p<0.05.
Inclusion Criteria:
- History of persistent atrial fibrillation
- Indicated for an AF-ablation procedure
- Agree to participate in the trial
Exclusion Criteria:
- Are unable or unwilling to provide informed consent for the SIMPle AF study
- Patients with cardiac devices like pacemakers, internal cardiac defibrillators and
Cardiac Resynchronization Therapy Device (CRT). Patients with acute or chronic renal
insufficiency (glomerular filtration rate <30 ml/min/1.73 m2), or patients in the
perioperative liver transplantation period
- Pregnant women
- Patients who are unable to adhere to the follow up protocol
- Patients with contraindication to MRI, including ferromagnetic aneurysm clips, metal
in the eye, and implanted ferromagnetic or other MRI-incompatible devices
- Patients in whom the LGE Cardiac MRI does not meet quality standards for fibrosis
analysis
- Subjects without daily access to a smart phone or tablet compatible with the
mobile-based application and ability to upload ECG tracings for the follow up period
- Patients with a history of allergic reactions to gadolinium-based contrast agents or
ingredients and will not be premedicated**
- Subjects with a history of reaction to contrast may be premedicated according to
institutional protocol prior to receiving intravenous contrast agents
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